rs104894820

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The NM_000166.6(GJB1):c.37G>A(p.Val13Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,208,459 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 5 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.97

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 Uncertain_significance. Variant got 2 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6 linkuse as main transcript	c.37G>A	p.Val13Met	missense_variant	2/2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 linkuse as main transcript	c.37G>A	p.Val13Met	missense_variant	2/2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 linkuse as main transcript	c.37G>A	p.Val13Met	missense_variant	2/2		XP_011529209.1	P08034A0A654ICJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 linkuse as main transcript	c.37G>A	p.Val13Met	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.0000538

AC:

AN:

111534

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33740

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000382

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

182766

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

67404

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000328

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1096925

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

362319

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000256

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000832

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000538

AC:

AN:

111534

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33740

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.000382

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000121

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	The c.37G>A;p.(Val13Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 637129; PMID: 22944031) - PS4_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Connexin) - PM1. The variant is present at low allele frequencies population databases (rs104894820 - gnomAD 0.0006019%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 10439 - c.37G>T;p.(Val13Leu); PMID: 27544631 - p.(Val13Glu)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, flagged submission

literature only

Inherited Neuropathy Consortium

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2020

The p.V13M variant (also known as c.37G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 37. The valine at codon 13 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in a small number of individuals who are described as carrying a diagnosis of Charcot-Marie-Tooth neuropathy (Bone LJ et al. Neurobiol Dis, 1997;4:221-30; Liu L et al. Clin Genet, 2017 Jun;91:881-891; Panosyan FB et al. Neurology, 2017 Aug;89:927-935). Based on data from gnomAD, the A allele has an overall frequency of 0.006% (11/182,766) total alleles studied, with 2 hemizygotes observed. The highest observed frequency was 0.033% (9/27,415) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 09, 2023

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

provider interpretation

Inherited Neuropathy Consortium

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.70

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

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

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

H;H;H;H;.;.;H

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.7

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

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.89

MutPred

0.95

Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);

MVP

1.0

MPC

1.8

ClinPred

0.63

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.95

gMVP

0.98

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