Human Gene Module / Chromosome 9 / HNRNPK

HNRNPKheterogeneous nuclear ribonucleoprotein K

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
2 / 12
Rare Variants / Common Variants
34 / 0
Aliases
HNRNPK, AUKS,  CSBP,  HNRPK,  TUNP
Associated Syndromes
Au-Kline syndrome, Okamoto syndrome
Chromosome Band
9q21.32
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

Gillentine et al., 2021 reported 13 previously unpublished individuals with variants in the HNRNPK gene, including an ASD proband from the SPARK cohort; a total of five individuals from this cohort presented with autism spectrum disorder, including two individuals with de novo likely gene-disruptive (LGD) variants and two individuals with de novo missense variants with CADD scores greater than 20 in HNRNPK. A proband with a de novo HNRNPK missense variant from the Deciphering Developmental Disorders study that was originally described in Kaplanis et al., 2020 was subsequently reported in Gillentine et al., 2021 to also present with autism spectrum disorder.

Molecular Function

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene is located in the nucleoplasm and has three repeats of KH domains that binds to RNAs. It is distinct among other hnRNP proteins in its binding preference; it binds tenaciously to poly(C). This protein is also thought to have a role during cell cycle progession. Heterozygous mutations in the HNRNPK gene are responsible for Au-Kline syndrome (OMIM 616580), a neurodevelopmental disorder characterized by developmental delay and

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HNRNPK (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Au PYB et al. (2015) No DD, ID
2 Support - Lange L et al. (2016) No DD
3 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No Epilepsy/seizures
4 Support - Dentici ML et al. (2018) No DD
5 Support - Miyake N et al. (2017) No DD
6 Support - Au PYB et al. (2018) No DD
7 Support - Okamoto N et al. (2019) No DD, ID
8 Support - Maystadt I et al. (2020) No DD
9 Support - Yamada M et al. (2020) No DD, ID
10 Support - Kaplanis J et al. (2020) No ASD
11 Primary - Gillentine MA et al. (2021) Yes -
12 Support - Axel Schmidt et al. (2024) Yes -
Rare Variants   (34)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.176G>A p.Gly59Glu missense_variant De novo - - 28135719 et al. (2017)
c.936+1G>A - splice_site_variant De novo - - 29904177 Au PYB et al. (2018)
c.859C>T p.Arg287Ter stop_gained De novo - - 29904177 Au PYB et al. (2018)
c.214-35A>G - intron_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1289+1G>A - splice_site_variant De novo - - 30793470 Okamoto N et al. (2019)
c.1109-13T>C - intron_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.157-10T>G - intron_variant De novo - Simplex 32588992 Yamada M et al. (2020)
c.85dup p.Glu29GlyfsTer6 frameshift_variant De novo - - 28135719 et al. (2017)
c.881+1dup - splice_site_variant De novo - Simplex 26173930 Au PYB et al. (2015)
c.707dup p.Asp238Ter frameshift_variant De novo - - 29904177 Au PYB et al. (2018)
c.1036+1G>T - splice_site_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.199G>C p.Ala67Pro missense_variant De novo - - 33057194 Kaplanis J et al. (2020)
c.253G>A p.Glu85Lys missense_variant De novo - - 33057194 Kaplanis J et al. (2020)
c.331-502G>A - splice_site_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.258-3C>T - splice_region_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1192-3C>A - splice_region_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.257+5G>A - splice_site_variant De novo - Simplex 32222014 Maystadt I et al. (2020)
c.65G>A p.Arg22His missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.253G>A p.Glu85Lys missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1225C>T p.Arg409Trp missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.443G>T p.Arg148Met missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.986C>T p.Pro329Leu missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.989G>A p.Gly330Glu missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.257G>A p.Arg86His missense_variant De novo - Multiplex 26173930 Au PYB et al. (2015)
c.1184C>T p.Pro395Leu missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.464T>C p.Leu155Pro missense_variant De novo - Simplex 28771707 Miyake N et al. (2017)
c.931_932insTT p.Pro311LeufsTer40 frameshift_variant De novo - - 28135719 et al. (2017)
c.1009del p.Val337LeufsTer13 frameshift_variant De novo - - 29904177 Au PYB et al. (2018)
c.1022del p.Gly341ValfsTer28 frameshift_variant De novo - - 29904177 Au PYB et al. (2018)
c.926dup p.Tyr309Ter frameshift_variant De novo - Simplex 28374925 Dentici ML et al. (2018)
c.99del p.Phe33LeufsTer25 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1290-35_1290-34insAAAG - frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1040_1041del p.Ser347CysfsTer15 frameshift_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.931_932insTT p.Pro311LeufsTer40 frameshift_variant De novo - Simplex 26954065 Lange L et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
2S

Increased from to 2S

Krishnan Probability Score

Score 0.57185286846131

Ranking 746/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99978238894903

Ranking 789/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.92853977250136

Ranking 10940/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.28877401335502

Ranking 2901/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Submit New Gene

Report an Error