2-178461008-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001042702.5(PJVK):c.793C>T(p.Arg265Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,613,510 control chromosomes in the GnomAD database, including 4,575 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. R265G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.054 (314 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4261 hom.)
• Consequence: PJVK NM_001042702.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.20

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028128922).
• BP6: Variant 2-178461008-C-T is Benign according to our data. Variant chr2-178461008-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43871.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr2-178461008-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PJVK	NM_001042702.5	c.793C>T	p.Arg265Cys	missense_variant	7/7	ENST00000644580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJVK	ENST00000644580.2	c.793C>T	p.Arg265Cys	missense_variant	7/7		NM_001042702.5	P1

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8290 AN: 152044 Hom.: 314 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0525

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0507

GnomAD3 exomes AF: 0.0561 AC: 13990 AN: 249418 Hom.: 513 AF XY: 0.0562 AC XY: 7605 AN XY: 135336

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.0540

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.0734

Gnomad NFE exome AF: 0.0816

Gnomad OTH exome AF: 0.0634

GnomAD4 exome AF: 0.0713 AC: 104255 AN: 1461348 Hom.: 4261 Cov.: 33 AF XY: 0.0703 AC XY: 51081 AN XY: 726976

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.0417

Gnomad4 ASJ exome AF: 0.0512

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.0739

Gnomad4 NFE exome AF: 0.0815

Gnomad4 OTH exome AF: 0.0631

GnomAD4 genome AF: 0.0545 AC: 8286 AN: 152162 Hom.: 314 Cov.: 32 AF XY: 0.0534 AC XY: 3969 AN XY: 74386

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.0524

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0745

Gnomad4 NFE AF: 0.0833

Gnomad4 OTH AF: 0.0501

Alfa AF: 0.0714 Hom.: 382

TwinsUK AF: 0.0785 AC: 291

ALSPAC AF: 0.0654 AC: 252

ESP6500AA AF: 0.0175 AC: 65

ESP6500EA AF: 0.0837 AC: 687

ExAC AF: 0.0580 AC: 7001

EpiCase AF: 0.0829

EpiControl AF: 0.0779

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 26, 2011	The Arg265Cys variant in DFNB59 is not expected to have clinical significance du e to its equal occurrence in probands and controls (Hashemzadeh-Chaleshtori 2007 , dbSNP-rs17304212). -

Autosomal recessive nonsyndromic hearing loss 59 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.93	D;D
PrimateAI	Benign	0.33	T
Polyphen		0.99	.;D;.;D;.;.;.;D
Vest4		0.22, 0.10
MPC		0.50
ClinPred		0.015	T
GERP RS		6.0
Varity_R		0.11
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17304212; hg19: chr2-179325735; COSMIC: COSV51845990; COSMIC: COSV51845990;