rs199626569

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1PM2PP2PP3BP4_Strong

The NM_000166.6(GJB1):c.497T>G(p.Val166Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.00016 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 8.02

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease X-linked dominant 1
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
X-linked progressive cerebellar ataxia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GJB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000166.6

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.019070834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.497T>G	p.Val166Gly	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.497T>G	p.Val166Gly	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	NM_001440770.1 link	c.497T>G	p.Val166Gly	missense_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 link	c.497T>G	p.Val166Gly	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00109

AC:

176

AN:

161923

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00196

Gnomad AMR exome

AF:

0.000833

Gnomad ASJ exome

AF:

0.000142

Gnomad EAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.000965

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000730

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000164

AC:

178

AN:

1086803

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356549

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000422

AC:

AN:

26051

American (AMR)

AF:

0.00165

AC:

AN:

33355

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19122

East Asian (EAS)

AF:

0.00143

AC:

AN:

29420

South Asian (SAS)

AF:

0.0000377

AC:

AN:

53039

European-Finnish (FIN)

AF:

0.000747

AC:

AN:

37466

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000358

AC:

AN:

838545

Other (OTH)

AF:

0.000197

AC:

AN:

45679

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.319

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000167

Hom.:

ExAC

AF:

0.00327

AC:

396

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 23, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Uncertain:1

Oct 28, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D;D

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.63

.;.;.;.;T

MetaRNN

Benign

0.019

T;T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;M;M;M;M

PhyloP100

8.0

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-6.7

D;.;D;.;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0070

D;.;D;.;D

Sift4G

Uncertain

0.0040

D;.;D;.;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.57

MVP

0.93

MPC

2.1

ClinPred

0.072

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.90

gMVP

1.0

Mutation Taster

=5/95

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over