rs17304212

chr2-178461008-C-Gchr2-178461008-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>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. 14/20 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. 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
• 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=0.0028193295).
• 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 id is 43870.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}.
• 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/exons	MANE	UniProt
PJVK	NM_001042702.5	c.793C>G	p.Arg265Gly	missense_variant	7/7	ENST00000644580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJVK	ENST00000644580.2	c.793C>G	p.Arg265Gly	missense_variant	7/7		NM_001042702.5	P1

Frequencies

GnomAD3 genomes AF: 0.0558 AC: 8479 AN: 152042 Hom.: 270 Cov.: 32

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

GnomAD3 exomes AF: 0.0558 AC: 13912 AN: 249418 Hom.: 463 AF XY: 0.0580 AC XY: 7852 AN XY: 135336

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 SAS exome AF: 0.0551

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.: 33 AF XY: 0.0653 AC XY: 47476 AN XY: 726930

Gnomad4 AFR exome AF: 0.0385

Gnomad4 AMR exome AF: 0.0339

Gnomad4 ASJ exome AF: 0.0512

Gnomad4 EAS exome AF: 0.00821

Gnomad4 SAS exome AF: 0.0565

Gnomad4 FIN exome AF: 0.0791

Gnomad4 NFE exome AF: 0.0700

Gnomad4 OTH exome AF: 0.0614

GnomAD4 genome AF: 0.0558 AC: 8486 AN: 152160 Hom.: 270 Cov.: 32 AF XY: 0.0559 AC XY: 4160 AN XY: 74376

Gnomad4 AFR AF: 0.0400

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.00443

Gnomad4 SAS AF: 0.0542

Gnomad4 FIN AF: 0.0865

Gnomad4 NFE AF: 0.0682

Gnomad4 OTH AF: 0.0610

Alfa AF: 0.00658 Hom.: 382

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:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 26, 2011	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

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	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.29	T
Polyphen		0.27	.;B;.;B;.;.;.;B
Vest4		0.20, 0.18
MPC		0.21
ClinPred		0.010	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs17304212; hg19: chr2-179325735; COSMIC: COSV51846203; COSMIC: COSV51846203;