2-178456149-C-T

Position:

chr2-178456149-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001042702.5(PJVK):c.547C>T(p.Arg183Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PJVK
NM_001042702.5 missense, splice_region

Scores

Splicing: ADA: 0.5815

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.43

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-178456150-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

PP5

Variant 2-178456149-C-T is Pathogenic according to our data. Variant chr2-178456149-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178456149-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PJVK	NM_001042702.5 linkuse as main transcript	c.547C>T	p.Arg183Trp	missense_variant, splice_region_variant	4/7	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.547C>T	p.Arg183Trp	missense_variant, splice_region_variant	4/7		NM_001042702.5	ENSP00000495855.2		Q0ZLH3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248764

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134946

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461420

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2024	Published functional studies demonstrate a damaging effect resulting in conduction anomalies and reduced amplitudes of ABR waves compared to wildtype (PMID: 16804542); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27344577, 30582396, 17373699, 34426522, 35052489, 16804542, 35982127) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the DFNB59 protein (p.Arg183Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 16804542, 17373699, 27344577). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1297). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DFNB59 function (PMID: 16804542). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Autosomal recessive nonsyndromic hearing loss 59

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2024	Variant summary: PJVK c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the Gasdermin, pore forming domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. Three predict the variant creates a cryptic 5' donor site. The variant allele was found at a frequency of 7.1e-06 in 280146 control chromosomes. c.547C>T has been reported in the literature in multiple individuals affected with Auditory neuropathy (example: Delmaghani_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental studies that this missense change affects protein function (example: Delmaghani_2006). The following publication has been ascertained in the context of this evaluation (PMID: 16804542).ClinVar contains an entry for this variant (Variation ID: 1297). Based on the evidence outlined above, the variant was classified as pathogenic. -

Ear malformation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

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

Eigen

Benign

0.087

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;M;.;.;M;.;.;.;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.6

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

REVEL

Uncertain

0.43

Sift

Uncertain

0.0080

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.98

MutPred

0.84

.;Loss of disorder (P = 0.0364);.;.;Loss of disorder (P = 0.0364);.;Loss of disorder (P = 0.0364);.;Loss of disorder (P = 0.0364);

MVP

0.22

MPC

0.46

ClinPred

0.94

GERP RS

-0.64

Varity_R

0.23

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.58

dbscSNV1_RF

Benign

0.54

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.80

Position offset: -2

DS_DL_spliceai

0.66

Position offset: 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