NM_000166.6:c.830G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBP6BS2

The NM_000166.6(GJB1):c.830G>A(p.Ser277Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000707 in 1,188,349 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 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. S277S) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000075 ( 0 hom. 32 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.82

Publications

1 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 -4 ACMG points.

PM1

In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 184 pathogenic changes around while only 11 benign (94%) 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=0.14532852).

BP6

Variant X-71224537-G-A is Benign according to our data. Variant chrX-71224537-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 543924.

BS2

High Hemizygotes in GnomAdExome4 at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.830G>A	p.Ser277Asn	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.830G>A	p.Ser277Asn	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	NM_001440770.1 link	c.830G>A	p.Ser277Asn	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.830G>A	p.Ser277Asn	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000432

AC:

AN:

138854

AF XY:

0.0000690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000426

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000865

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000752

AC:

AN:

1076545

Hom.:

Cov.:

AF XY:

0.0000916

AC XY:

AN XY:

349297

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25846

American (AMR)

AF:

0.0000309

AC:

AN:

32352

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18960

East Asian (EAS)

AF:

0.00

AC:

AN:

28955

South Asian (SAS)

AF:

0.00

AC:

AN:

51507

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38243

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

0.0000926

AC:

AN:

831257

Other (OTH)

AF:

0.0000662

AC:

AN:

45323

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000268

AC:

AN:

111804

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33968

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30731

American (AMR)

AF:

0.00

AC:

AN:

10547

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3516

South Asian (SAS)

AF:

0.00

AC:

AN:

2684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6127

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53118

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000255

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.830G>A (p.S277N) alteration is located in exon 2 (coding exon 1) of the GJB1 gene. This alteration results from a G to A substitution at nucleotide position 830, causing the serine (S) at amino acid position 277 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Sep 23, 2022

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Computational tools predict that this variant is not damaging. -

Charcot-Marie-Tooth disease

Benign:1

Oct 28, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Feb 22, 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

0.090

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.22

T;T;T;T;T

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.78

.;.;.;.;T

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

-0.34

N;N;N;N;N

PhyloP100

3.8

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.32

N;.;N;.;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

T;.;T;.;T

Sift4G

Benign

0.40

T;.;T;.;T

Polyphen

0.0020

B;B;B;B;B

Vest4

0.093

MVP

0.78

MPC

0.72

ClinPred

0.092

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.55

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

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