rs200674715

Positions:

chr13-20222874-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110219.3(GJB6):c.607A>G(p.Met203Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,614,076 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 3 hom. )

Consequence

GJB6
NM_001110219.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.55

Variant links:

Genes affected

GJB6 (HGNC:4288): (gap junction protein beta 6) Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

GJB6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01564446).

BP6

Variant 13-20222874-T-C is Benign according to our data. Variant chr13-20222874-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 45505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20222874-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000802 (122/152198) while in subpopulation NFE AF= 0.000852 (58/68038). AF 95% confidence interval is 0.000677. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB6	NM_001110219.3 linkuse as main transcript	c.607A>G	p.Met203Val	missense_variant	5/5	ENST00000647029.1	NP_001103689.1	O95452A0A024RDS4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB6	ENST00000647029.1 linkuse as main transcript	c.607A>G	p.Met203Val	missense_variant	5/5		NM_001110219.3	ENSP00000493834.1		O95452

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152198

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:

0.00603

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000852

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000736

AC:

185

AN:

251404

Hom.:

AF XY:

0.000721

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00550

Gnomad NFE exome

AF:

0.000537

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000412

AC:

602

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

315

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00492

Gnomad4 NFE exome

AF:

0.000289

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000802

AC:

122

AN:

152198

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74360

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:

0.00603

Gnomad4 NFE

AF:

0.000852

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000610

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 22, 2011	Met203Val in exon 3 of GJB6: This variant is not expected to have clinical signi ficance. It has been identified in 1% (2/214) of a population studied for suscep tibility to noise, but did not include childhood hearing loss patients (Carlsson 2007). In addition, this variant is not conserved across all species and comput ational analyses (biochemical amino acid properties, PolyPhen2, SIFT, AlignGVGD) do not predict an impact to the protein. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2022	Variant summary: GJB6 c.607A>G (p.Met203Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 251404 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4700 fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB6 causing Hidrotic Ectodermal Dysplasia Syndrome phenotype (1.6e-07), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Hidrotic ectodermal dysplasia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hidrotic ectodermal dysplasia syndrome;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

GJB6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Uncertain

0.54

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

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.016

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

MetaSVM

Uncertain

0.037

MutationAssessor

Benign

-0.060

N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

0.99

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

REVEL

Uncertain

0.54

Sift

Benign

0.090

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

Sift4G

Benign

0.19

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

Polyphen

0.016

B;B;B;B;B;B;B;B;B;B;B

Vest4

0.70

MVP

0.67

MPC

0.097

ClinPred

0.023

GERP RS

1.9

Varity_R

0.11

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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