rs79399438

chr2-178461089-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (86 hom., cov: 32)
  • Exomes 𝑓: 0.026 (811 hom.)
• Consequence: PJVK NM_001042702.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.52

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr2-178461089-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
PJVK	NM_001042702.5	c.874G>A	p.Gly292Arg	missense_variant	7/7	ENST00000644580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJVK	ENST00000644580.2	c.874G>A	p.Gly292Arg	missense_variant	7/7		NM_001042702.5	P1

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4127 AN: 152054 Hom.: 87 Cov.: 32

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

GnomAD3 exomes AF: 0.0283 AC: 7062 AN: 249520 Hom.: 208 AF XY: 0.0271 AC XY: 3662 AN XY: 135368

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 SAS exome AF: 0.00703

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.: 32 AF XY: 0.0254 AC XY: 18483 AN XY: 727208

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0206

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.00761

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.0241

Gnomad4 OTH exome AF: 0.0299

GnomAD4 genome AF: 0.0271 AC: 4130 AN: 152172 Hom.: 86 Cov.: 32 AF XY: 0.0263 AC XY: 1958 AN XY: 74394

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.0196

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0270 Hom.: 157

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 59 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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	T
BayesDel_noAF	Benign	-0.52
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	0.0046	P;P
PrimateAI	Uncertain	0.61	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	T
GERP RS		5.9
Varity_R		0.18
gMVP		0.56

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

LitVar

Other links and lift over

dbSNP: rs79399438; hg19: chr2-179325816; COSMIC: COSV51845540; COSMIC: COSV51845540;