rs17304212

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 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 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

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 links:

PJVK (HGNC:):

PJVK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=1, Benign=5}.

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	Protein	UniProt
PJVK	NM_001042702.5 linkuse as main transcript	c.793C>G	p.Arg265Gly	missense_variant	7/7	ENST00000644580.2	NP_001036167.1	Q0ZLH3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2 linkuse as main transcript	c.793C>G	p.Arg265Gly	missense_variant	7/7		NM_001042702.5	ENSP00000495855.2		Q0ZLH3

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

GnomAD3 exomes

AF:

0.0558

AC:

13912

AN:

249418

Hom.:

463

AF XY:

0.0580

AC XY:

7852

AN XY:

135336

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 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.:

AF XY:

0.0653

AC XY:

47476

AN XY:

726930

show subpopulations

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.:

AF XY:

0.0559

AC XY:

4160

AN XY:

74376

show subpopulations

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:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Autosomal recessive nonsyndromic hearing loss 59

Uncertain:1Benign: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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over