rs771579861

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP6_Moderate

The NM_000166.6(GJB1):c.574G>A(p.Val192Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,205,553 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V192F) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000091 ( 0 hom. 1 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 5.57

Publications

4 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, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
X-linked progressive cerebellar ataxia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GJB1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000166.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 9 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 X-linked progressive cerebellar ataxia, Charcot-Marie-Tooth disease X-linked dominant 1.

BP6

Variant X-71224281-G-A is Benign according to our data. Variant chrX-71224281-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 862759.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000166.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJB1	NM_000166.6	MANE Select	c.574G>A	p.Val192Ile	missense	Exon 2 of 2	NP_000157.1	P08034
GJB1	NM_001097642.3		c.574G>A	p.Val192Ile	missense	Exon 2 of 2	NP_001091111.1	P08034
GJB1	NM_001440770.1		c.574G>A	p.Val192Ile	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJB1	ENST00000361726.7	TSL:1 MANE Select	c.574G>A	p.Val192Ile	missense	Exon 2 of 2	ENSP00000354900.6	P08034
GJB1	ENST00000374029.2	TSL:5	c.574G>A	p.Val192Ile	missense	Exon 2 of 2	ENSP00000363141.1	P08034
GJB1	ENST00000447581.2	TSL:5	c.574G>A	p.Val192Ile	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes

AF:

0.0000273

AC:

AN:

109728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000999

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000221

AC:

AN:

181168

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.000229

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000913

AC:

AN:

1095825

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362201

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26399

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.000166

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

842011

Other (OTH)

AF:

0.00

AC:

AN:

46072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

AF:

0.0000273

AC:

AN:

109728

Hom.:

Cov.:

AF XY:

0.0000312

AC XY:

AN XY:

32040

show subpopulations

African (AFR)

AF:

0.0000999

AC:

AN:

30021

American (AMR)

AF:

0.00

AC:

AN:

10278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2615

East Asian (EAS)

AF:

0.00

AC:

AN:

3495

South Asian (SAS)

AF:

0.00

AC:

AN:

2495

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5857

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52594

Other (OTH)

AF:

0.00

AC:

AN:

1472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth Neuropathy X (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.31

DEOGEN2

Uncertain

0.59

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.76

MetaRNN

Uncertain

0.50

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

0.040

PhyloP100

5.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.10

REVEL

Uncertain

0.48

Sift

Benign

0.61

Sift4G

Benign

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.88

Mutation Taster

=100/0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over