rs104894823

Variant names:

• chrX-71223961-C-G
• rs104894823
• NM_000166.6:c.254C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-71223961-C-G
• chrX-71223961-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000166.6(GJB1):​c.254C>G​(p.Ser85Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S85F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• 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. GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-71223961-C-G is Pathogenic according to our data. Variant chrX-71223961-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 10444.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71223961-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.254C>G	p.Ser85Cys	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.254C>G	p.Ser85Cys	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	XM_011530907.3	c.254C>G	p.Ser85Cys	missense_variant	Exon 2 of 2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.254C>G	p.Ser85Cys	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate an increase in functional hemichannels and reduced protein expression (PMID: 11891346); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9099841, 11325342, 11891346) -

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:1

Mar 19, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;.;.;.;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;M;M;.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D;.;D;.;.;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.;D;.;.;D
Sift4G	Pathogenic	0.0010	D;.;D;.;.;D
Polyphen		1.0	D;D;D;D;.;D
Vest4		0.81
MutPred		0.96		Loss of glycosylation at S85 (P = 0.0248);Loss of glycosylation at S85 (P = 0.0248);Loss of glycosylation at S85 (P = 0.0248);Loss of glycosylation at S85 (P = 0.0248);Loss of glycosylation at S85 (P = 0.0248);Loss of glycosylation at S85 (P = 0.0248);
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.84
gMVP		0.98
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894823; hg19: chrX-70443811; COSMIC: COSV62139497; COSMIC: COSV62139497;