2-178460446-A-C

Position:

chr2-178460446-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001042702.5(PJVK):c.766A>C(p.Asn256His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000558 in 1,613,048 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PJVK
NM_001042702.5 missense, splice_region

Scores

Splicing: ADA: 0.5237

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24175581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PJVK	NM_001042702.5 linkuse as main transcript	c.766A>C	p.Asn256His	missense_variant, splice_region_variant	6/7	ENST00000644580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJVK	ENST00000644580.2 linkuse as main transcript	c.766A>C	p.Asn256His	missense_variant, splice_region_variant	6/7		NM_001042702.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249424

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135326

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460858

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 03, 2022	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 256 of the DFNB59 protein (p.Asn256His). This variant is present in population databases (rs727502958, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DFNB59-related conditions. ClinVar contains an entry for this variant (Variation ID: 163059). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 31, 2013

The Asn256His variant in DFNB59 has not been previously reported in individuals with hearing loss or observed in large population studies. Computational analyse s (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SI FT) do not provide strong support for or against an impact to the protein. In su mmary, additional data is needed to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.058

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

Eigen

Benign

-0.036

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

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

M_CAP

Benign

0.026

MetaRNN

Benign

0.24

T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.41

.;N;.;N;.;.;N

MutationTaster

Benign

0.80

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.59

.;.;.;N;.;.;N

REVEL

Benign

0.15

Sift

Benign

0.081

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

Sift4G

Benign

0.16

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

Polyphen

0.42

.;B;.;B;.;.;B

Vest4

0.65, 0.65

MutPred

0.39

.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;.;Gain of helix (P = 0.0325);

MVP

0.41

MPC

0.33

ClinPred

0.41

GERP RS

5.4

Varity_R

0.12

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.52

dbscSNV1_RF

Benign

0.55

SpliceAI score (max)

0.11

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