rs79399438

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042702.5(PJVK):c.874G>A(p.Gly292Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0261 in 1,613,996 control chromosomes in the GnomAD database, including 897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G292V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 86 hom., cov: 32)

Exomes 𝑓: 0.026 ( 811 hom. )

Consequence

PJVK
NM_001042702.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.52

Publications

20 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017353296).

BP6

Variant 2-178461089-G-A is Benign according to our data. Variant chr2-178461089-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PJVK	NM_001042702.5 link	c.874G>A	p.Gly292Arg	missense_variant	Exon 7 of 7	ENST00000644580.2	NP_001036167.1	Q0ZLH3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2 link	c.874G>A	p.Gly292Arg	missense_variant	Exon 7 of 7		NM_001042702.5	ENSP00000495855.2		Q0ZLH3

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4127

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0294

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.132

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0238

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0283

AC:

7062

AN:

249520

AF XY:

0.0271

show subpopulations

Gnomad AFR exome

AF:

0.0296

Gnomad AMR exome

AF:

0.0209

Gnomad ASJ exome

AF:

0.0190

Gnomad EAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0232

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0259

AC:

37934

AN:

1461824

Hom.:

811

Cov.:

AF XY:

0.0254

AC XY:

18483

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0263

AC:

881

AN:

33478

American (AMR)

AF:

0.0207

AC:

924

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

538

AN:

26132

East Asian (EAS)

AF:

0.142

AC:

5648

AN:

39682

South Asian (SAS)

AF:

0.00761

AC:

656

AN:

86254

European-Finnish (FIN)

AF:

0.0120

AC:

640

AN:

53414

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0241

AC:

26804

AN:

1111982

Other (OTH)

AF:

0.0299

AC:

1807

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2118

4236

6354

8472

10590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1120

2240

3360

4480

5600

<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:

0.0271

AC:

4130

AN:

152172

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

1958

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0293

AC:

1216

AN:

41488

American (AMR)

AF:

0.0196

AC:

300

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3472

East Asian (EAS)

AF:

0.133

AC:

687

AN:

5168

South Asian (SAS)

AF:

0.00664

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10590

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0238

AC:

1620

AN:

68018

Other (OTH)

AF:

0.0255

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

212

425

637

850

1062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0277

Hom.:

349

Bravo

AF:

0.0284

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.0293

AC:

109

ESP6500EA

AF:

0.0218

AC:

179

ExAC

AF:

0.0288

AC:

3475

Asia WGS

AF:

0.0660

AC:

230

AN:

3478

EpiCase

AF:

0.0204

EpiControl

AF:

0.0229

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 28, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly292Arg in Exon 07 of DFNB59: This variant is not expected to have clinical si gnificance because it has been identified in 2.9% (87/3024) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs79399438). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 08, 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. -

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 12, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive nonsyndromic hearing loss 59

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

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

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

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

MetaRNN

Benign

0.0017

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

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.81

.;L;.;L;.;.;.;L

PhyloP100

5.5

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.17

Sift

Uncertain

0.0070

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

Sift4G

Benign

0.12

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

Polyphen

0.88

.;P;.;P;.;.;.;P

Vest4

0.23, 0.15

MutPred

0.85

.;Loss of sheet (P = 0.0228);.;Loss of sheet (P = 0.0228);.;.;.;Loss of sheet (P = 0.0228);

MPC

0.23

ClinPred

0.015

GERP RS

5.9

Varity_R

0.18

gMVP

0.56

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over