rs748095080

Positions:

chrX-71224537-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The NM_000166.6(GJB1):c.830G>A(p.Ser277Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000707 in 1,188,349 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000075 ( 0 hom. 32 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.82

Variant links:

Genes affected

GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

GJB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000166.6

BP4

Computational evidence support a benign effect (MetaRNN=0.14532852).

BP6

Variant X-71224537-G-A is Benign according to our data. Variant chrX-71224537-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 543924.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAdExome4 at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GJB1	NM_000166.6 linkuse as main transcript	c.830G>A	p.Ser277Asn	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3 linkuse as main transcript	c.830G>A	p.Ser277Asn	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3 linkuse as main transcript	c.830G>A	p.Ser277Asn	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 linkuse as main transcript	c.830G>A	p.Ser277Asn	missense_variant	2/2	1	NM_000166.6	ENSP00000354900	P1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111804

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33968

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000432

AC:

AN:

138854

Hom.:

AF XY:

0.0000690

AC XY:

AN XY:

43466

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000426

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:

0.0000865

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000752

AC:

AN:

1076545

Hom.:

Cov.:

AF XY:

0.0000916

AC XY:

AN XY:

349297

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000309

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:

0.0000926

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111804

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33968

show subpopulations

Gnomad4 AFR

AF:

0.0000325

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:

0.0000377

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000255

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The p.S277N variant (also known as c.830G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 830. The serine at codon 277 is replaced by asparagine, an amino acid with highly similar properties. Based on data from the Genome Aggregation Database (gnomAD), the A allele has an overall frequency of approximately 0.004% (6/138854) total alleles studied, including a total of 3 hemizygotes. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 23, 2022

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Computational tools predict that this variant is not damaging. -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.22

T;T;T;T;T

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.78

.;.;.;.;T

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

-0.34

N;N;N;N;N

MutationTaster

Benign

0.88

N;N;N

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.32

N;.;N;.;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

0.40

T;.;T;.;T

Polyphen

0.0020

B;B;B;B;B

Vest4

0.093

MVP

0.78

MPC

0.72

ClinPred

0.092

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.55

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