rs104894812

Variant names:

• chrX-71224122-G-A
• rs104894812
• NM_000166.6:c.415G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.415G>A​(p.Val139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,092,662 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000658910: Experimental studies have shown that this missense change affects GJB1 function (PMID:8816997, 11325342)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V139G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1 O:1
• Conservation: PhyloP100: 2.65
• Publications: 24 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000658910: Experimental studies have shown that this missense change affects GJB1 function (PMID: 8816997, 11325342).; SCV005201160: Published functional studies demonstrate this variant exhibits no GJIC capacity function, it demonstrates dominant negative down-regulation of GJIC function when co-expressed with wild type, and it alters the formation and structure of gap junction plaques (PMID: 8816997, 28071741).; SCV002628080: Functional studies indicate that this alteration impairs gap junction formation and results in altered pattern of trafficking and localization (Omori Y et al. Mol Biol Cell, 1996 Jun;7:907-16; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; Abrams CK et al. Brain Res, 2001 May;900:9-25; Abrams CK et al. Sci Rep, 2017 01;7:40166).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71224123-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1416909.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant X-71224122-G-A is Pathogenic according to our data. Variant chrX-71224122-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.415G>A	p.Val139Met	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.415G>A	p.Val139Met	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.415G>A	p.Val139Met	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.415G>A	p.Val139Met	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.415G>A	p.Val139Met	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.415G>A	p.Val139Met	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000584 AC: 1 AN: 171137 AF XY: 0.00

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: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092662 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 358430

African (AFR) AF: 0.00 AC: 0 AN: 26347

American (AMR) AF: 0.00 AC: 0 AN: 34640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19266

East Asian (EAS) AF: 0.00 AC: 0 AN: 30073

South Asian (SAS) AF: 0.00 AC: 0 AN: 53202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40217

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838878

Other (OTH) AF: 0.00 AC: 0 AN: 45909

GnomAD4 genome Cov.: 22

Alfa AF: 0.000143 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Charcot-Marie-Tooth disease X-linked dominant 1 (5)
3	-	-	not provided (3)
-	1	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth Neuropathy X (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.010	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.58
MutPred		0.86		Gain of MoRF binding (P = 0.0988)
MVP		0.98
MPC		1.6
ClinPred		0.69	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.95
Mutation Taster		=5/95	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

Other links and lift over

dbSNP: rs104894812; hg19: chrX-70443972;