rs753503984

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2

The NM_000166.6(GJB1):c.637A>G(p.Ile213Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000995 in 1,205,979 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 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). Synonymous variant affecting the same amino acid position (i.e. I213I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.00011 ( 0 hom. 36 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 2.32

Publications

7 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: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000166.6

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.29209244).

BP6

Variant X-71224344-A-G is Benign according to our data. Variant chrX-71224344-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521767.

BS2

High Hemizygotes in GnomAdExome4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.637A>G	p.Ile213Val	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.637A>G	p.Ile213Val	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	NM_001440770.1 link	c.637A>G	p.Ile213Val	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.637A>G	p.Ile213Val	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.0000366

AC:

AN:

109361

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000335

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:

0.0000571

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000222

AC:

AN:

180398

AF XY:

0.0000307

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000494

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

116

AN:

1096618

Hom.:

Cov.:

AF XY:

0.0000994

AC XY:

AN XY:

362260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19364

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39397

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000138

AC:

116

AN:

841819

Other (OTH)

AF:

0.00

AC:

AN:

46062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000366

AC:

AN:

109361

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31825

show subpopulations

African (AFR)

AF:

0.0000335

AC:

AN:

29895

American (AMR)

AF:

0.00

AC:

AN:

10199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2619

East Asian (EAS)

AF:

0.00

AC:

AN:

3452

South Asian (SAS)

AF:

0.00

AC:

AN:

2495

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

231

European-Non Finnish (NFE)

AF:

0.0000571

AC:

AN:

52578

Other (OTH)

AF:

0.00

AC:

AN:

1456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000585

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Uncertain:3

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 09, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:2

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 05, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

May 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Uncertain

0.62

D;D;D;D;D

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.76

.;.;.;.;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Uncertain

-0.089

MutationAssessor

Benign

0.34

N;N;N;N;N

PhyloP100

2.3

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.27

N;.;N;.;N

REVEL

Uncertain

0.53

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

0.94

T;.;T;.;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.071

MVP

0.99

MPC

0.64

ClinPred

0.043

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.087

gMVP

0.89

Mutation Taster

=71/29

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over