rs17304212

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001042702.5(PJVK):c.793C>G(p.Arg265Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,613,372 control chromosomes in the GnomAD database, including 3,702 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.056 ( 270 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3432 hom. )

Consequence

PJVK
NM_001042702.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.20

Publications

22 publications found

Variant links:

Genes affected

PJVK (HGNC:29502): (pejvakin) The protein encoded by this gene is a member of the gasdermin family, a family which is found only in vertebrates. The encoded protein is required for the proper function of auditory pathway neurons. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal recessive type 59 (DFNB59). [provided by RefSeq, Dec 2008]

PJVK Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 59
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PJVK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028193295).

BP6

Variant 2-178461008-C-G is Benign according to our data. Variant chr2-178461008-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43870.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PJVK	NM_001042702.5 link	c.793C>G	p.Arg265Gly	missense_variant	Exon 7 of 7	ENST00000644580.2	NP_001036167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2 link	c.793C>G	p.Arg265Gly	missense_variant	Exon 7 of 7		NM_001042702.5	ENSP00000495855.2

Frequencies

GnomAD3 genomes

AF:

0.0558

AC:

8479

AN:

152042

Hom.:

270

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0399

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0434

Gnomad ASJ

AF:

0.0510

Gnomad EAS

AF:

0.00442

Gnomad SAS

AF:

0.0540

Gnomad FIN

AF:

0.0865

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0682

Gnomad OTH

AF:

0.0621

GnomAD2 exomes

AF:

0.0558

AC:

13912

AN:

249418

AF XY:

0.0580

show subpopulations

Gnomad AFR exome

AF:

0.0385

Gnomad AMR exome

AF:

0.0327

Gnomad ASJ exome

AF:

0.0509

Gnomad EAS exome

AF:

0.00484

Gnomad FIN exome

AF:

0.0824

Gnomad NFE exome

AF:

0.0684

Gnomad OTH exome

AF:

0.0639

GnomAD4 exome

AF:

0.0653

AC:

95399

AN:

1461212

Hom.:

3432

Cov.:

AF XY:

0.0653

AC XY:

47476

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.0385

AC:

1290

AN:

33474

American (AMR)

AF:

0.0339

AC:

1514

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0512

AC:

1338

AN:

26130

East Asian (EAS)

AF:

0.00821

AC:

326

AN:

39684

South Asian (SAS)

AF:

0.0565

AC:

4866

AN:

86198

European-Finnish (FIN)

AF:

0.0791

AC:

4214

AN:

53274

Middle Eastern (MID)

AF:

0.0626

AC:

361

AN:

5764

European-Non Finnish (NFE)

AF:

0.0700

AC:

77783

AN:

1111582

Other (OTH)

AF:

0.0614

AC:

3707

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

4519

9039

13558

18078

22597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2854

5708

8562

11416

14270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0558

AC:

8486

AN:

152160

Hom.:

270

Cov.:

AF XY:

0.0559

AC XY:

4160

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0400

AC:

1659

AN:

41524

American (AMR)

AF:

0.0433

AC:

662

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0510

AC:

177

AN:

3472

East Asian (EAS)

AF:

0.00443

AC:

AN:

5190

South Asian (SAS)

AF:

0.0542

AC:

262

AN:

4830

European-Finnish (FIN)

AF:

0.0865

AC:

912

AN:

10548

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0682

AC:

4637

AN:

67988

Other (OTH)

AF:

0.0610

AC:

129

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

397

795

1192

1590

1987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00491

Hom.:

497

TwinsUK

AF:

0.0704

AC:

261

ALSPAC

AF:

0.0641

AC:

247

ExAC

AF:

0.0553

AC:

6682

EpiCase

AF:

0.0690

EpiControl

AF:

0.0684

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 26, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg265Gly variant in DFNB59 has been reported in 4/30 probands with SNHL and 17/200 control chromosomes (Hashmzadeh-Chaleshtori, 2007), and was reported at a frequency of 1.7% in the Yoruba population in dbSNP (rs17304212). Therefore, t his variant is not expected to have clinical significance due to equal occurrenc e in probands and controls. -

Aug 18, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 59

Uncertain:1Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

.;T;.;T;.;.;.;T

Eigen

Benign

0.082

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

.;.;.;.;.;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;N;.;N;.;.;.;N

PhyloP100

2.2

PrimateAI

Benign

0.29

PROVEAN

Benign

0.38

.;.;.;N;.;.;.;N

REVEL

Benign

0.18

Sift

Benign

0.035

.;.;.;D;.;.;.;D

Sift4G

Benign

0.21

.;.;.;T;.;.;.;T

Polyphen

0.27

.;B;.;B;.;.;.;B

Vest4

0.20, 0.18

MPC

0.21

ClinPred

0.010

GERP RS

6.0

Varity_R

0.12

gMVP

0.41

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over