Genetic Variant HNRNPK:p.Glu428Lys (chr9-83970241-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_031263.4(HNRNPK):c.1282G>A(p.Glu428Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

HNRNPK
NM_031263.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.60

Publications

0 publications found

Variant links:

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]

HNRNPK links:

HNRNPK-AS1 (HGNC:56061): (HNRNPK antisense RNA 1)

HNRNPK-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the HNRNPK gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 3.9922 (above the threshold of 3.09). Trascript score misZ: 3.2967 (above the threshold of 3.09). GenCC associations: The gene is linked to Au-Kline syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome.

PP5

Variant 9-83970241-C-T is Pathogenic according to our data. Variant chr9-83970241-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1077160.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNRNPK	NM_031263.4	MANE Select	c.1282G>A	p.Glu428Lys	missense	Exon 16 of 17	NP_112553.1	P61978-2
HNRNPK	NM_002140.5		c.1282G>A	p.Glu428Lys	missense	Exon 16 of 17	NP_002131.2
HNRNPK	NM_001318188.2		c.1282G>A	p.Glu428Lys	missense	Exon 16 of 17	NP_001305117.1	P61978-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNRNPK	ENST00000376263.8	TSL:1 MANE Select	c.1282G>A	p.Glu428Lys	missense	Exon 16 of 17	ENSP00000365439.3	P61978-2
HNRNPK	ENST00000376281.8	TSL:1	c.1282G>A	p.Glu428Lys	missense	Exon 16 of 17	ENSP00000365458.4	P61978-2
HNRNPK	ENST00000360384.9	TSL:1	c.1282G>A	p.Glu428Lys	missense	Exon 16 of 17	ENSP00000353552.5	P61978-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Au-Kline syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

5.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.5

REVEL

Benign

0.23

Sift

Benign

0.046

Sift4G

Benign

0.070

Polyphen

0.69

Vest4

0.62

MutPred

0.65

Gain of ubiquitination at E428 (P = 0.0104)

MVP

0.69

MPC

1.5

ClinPred

0.82

GERP RS

5.3

Varity_R

0.62

gMVP

0.91

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over