Variant rs761350704 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The ENST00000361726.7(GJB1):c.449T>C(p.Met150Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,092,821 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M150R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

GJB1
ENST00000361726.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.02

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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, 13 uncertain in ENST00000361726.7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GJB1	NM_000166.6 linkuse as main transcript	c.449T>C	p.Met150Thr	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3 linkuse as main transcript	c.449T>C	p.Met150Thr	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3 linkuse as main transcript	c.449T>C	p.Met150Thr	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 linkuse as main transcript	c.449T>C	p.Met150Thr	missense_variant	2/2	1	NM_000166.6	ENSP00000354900	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000594

AC:

AN:

168483

Hom.:

AF XY:

0.0000182

AC XY:

AN XY:

54943

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1092821

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

358821

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000188

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

D;D;D;D;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.70

.;.;.;.;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.5

M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

D;.;D;.;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.011

D;.;D;.;D

Sift4G

Uncertain

0.038

D;.;D;.;D

Polyphen

0.84

P;P;P;P;P

Vest4

0.78

MutPred

0.61

Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);

MVP

0.98

MPC

1.8

ClinPred

0.79

GERP RS

4.7

Varity_R

0.81

gMVP

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over