rs754963933

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1PP2BS2

The NM_000166.6(GJB1):c.505G>A(p.Asp169Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000374 in 1,203,606 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D169V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000039 ( 0 hom. 12 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 6.91

Publications

2 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 -1 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 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.

BS2

High Hemizygotes in GnomAdExome4 at 12 XL gene

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
GJB1	NM_000166.6	MANE Select	c.505G>A	p.Asp169Asn	missense	Exon 2 of 2	NP_000157.1
GJB1	NM_001097642.3		c.505G>A	p.Asp169Asn	missense	Exon 2 of 2	NP_001091111.1
GJB1	NM_001440770.1		c.505G>A	p.Asp169Asn	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GJB1	ENST00000361726.7	TSL:1 MANE Select	c.505G>A	p.Asp169Asn	missense	Exon 2 of 2	ENSP00000354900.6
GJB1	ENST00000374029.2	TSL:5	c.505G>A	p.Asp169Asn	missense	Exon 2 of 2	ENSP00000363141.1
GJB1	ENST00000447581.2	TSL:5	c.505G>A	p.Asp169Asn	missense	Exon 3 of 3	ENSP00000407223.2

Frequencies

GnomAD3 genomes

AF:

0.0000183

AC:

AN:

109544

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000381

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000115

AC:

AN:

173730

AF XY:

0.00

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:

0.0000257

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000393

AC:

AN:

1094062

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

360364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26363

American (AMR)

AF:

0.00

AC:

AN:

34973

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19303

East Asian (EAS)

AF:

0.00

AC:

AN:

30145

South Asian (SAS)

AF:

0.00

AC:

AN:

53649

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000511

AC:

AN:

841139

Other (OTH)

AF:

0.00

AC:

AN:

46002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.0000183

AC:

AN:

109544

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31804

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30003

American (AMR)

AF:

0.00

AC:

AN:

10317

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2616

East Asian (EAS)

AF:

0.00

AC:

AN:

3453

South Asian (SAS)

AF:

0.00

AC:

AN:

2457

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5845

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000381

AC:

AN:

52493

Other (OTH)

AF:

0.00

AC:

AN:

1460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

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

0.11

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.78

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

0.80

PhyloP100

6.9

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.69

REVEL

Uncertain

0.31

Sift

Benign

0.40

Sift4G

Benign

0.43

Polyphen

0.18

Vest4

0.14

MutPred

0.25

Gain of methylation at R164 (P = 0.1283)

MVP

0.83

MPC

0.86

ClinPred

0.30

GERP RS

4.8

Varity_R

0.22

gMVP

0.90

Mutation Taster

=56/44

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

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

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over