rs886041807

chr9-83972055-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_031263.4(HNRNPK):c.779_780insG(p.Asp262Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPK NM_031263.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.31

Genes affected

HNRNPK (HGNC:5044): (heterogeneous nuclear ribonucleoprotein K) 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. Several alternatively spliced transcript variants have been described for this gene, however, not all of them are fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-83972055-A-AC is Pathogenic according to our data. Variant chr9-83972055-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 280639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPK	NM_031263.4	c.779_780insG	p.Asp262Ter	frameshift_variant	11/17	ENST00000376263.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPK	ENST00000376263.8	c.779_780insG	p.Asp262Ter	frameshift_variant	11/17	1	NM_031263.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Au-Kline syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Research Group, University of Calgary	Jan 07, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2016

The c.779dupG pathogenic variant in the HNRNPK gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.779dupG variant causes a frameshift starting with codon Aspartic acid 262, and changes this amino acid to a premature Stop codon, denoted p.Asp262Ter. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.779dupG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.779dupG as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041807; hg19: chr9-86586970;