X-71223751-G-A

Variant names:

• chrX-71223751-G-A
• rs863224974
• NM_000166.6:c.44G>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.44G>A​(p.Arg15Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,733 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: "SCV000283687: Experimental studies have shown that this missense change affects GJB1 function (PMID:9364054, 11325342, 15006706)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.83
• Publications: 23 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: SCV000283687: Experimental studies have shown that this missense change affects GJB1 function (PMID: 9364054, 11325342, 15006706).; SCV000293139: Published functional studies demonstrate no affect on the expression and localization of the protein, but do show a moderate effect of the channel conductance (Shy et al., 2007; Deschenes et al., 1997; Abrams et al., 2001); SCV002639693: Functional studies of this variant have demonstrated proper protein localization and channel formation but some altered channel activity (Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; Abrams CK et al. Brain Res, 2001 May;900:9-25; Wang HL et al. Neurobiol Dis, 2004 Mar;15:361-70).; SCV004175227: Functional studies have demonstrated that the variant has no effect on protein localization and channel formation but does show moderate effect on channel conductance (PMID: 9364054, 11325342, 15006706) (PS3_moderate).; SCV005415908: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 28 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-71223751-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1709368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.946
• PP5: Variant X-71223751-G-A is Pathogenic according to our data. Variant chrX-71223751-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 217169.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.44G>A	p.Arg15Gln	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.44G>A	p.Arg15Gln	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.44G>A	p.Arg15Gln	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.44G>A	p.Arg15Gln	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.44G>A	p.Arg15Gln	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.44G>A	p.Arg15Gln	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096733 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362117

African (AFR) AF: 0.00 AC: 0 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840821

Other (OTH) AF: 0.00 AC: 0 AN: 46048

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Charcot-Marie-Tooth disease X-linked dominant 1 (3)
2	-	-	not provided (2)
1	-	-	Charcot-Marie-Tooth Neuropathy X (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.77	N
PhyloP100		3.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.82
Sift	Benign	0.062	T
Sift4G	Benign	0.094	T
Polyphen		0.99	D
Vest4		0.78
MutPred		0.85		Loss of MoRF binding (P = 0.0174)
MVP		0.99
MPC		1.8
ClinPred		0.88	D
GERP RS		4.4
Varity_R		0.72
gMVP		0.95
Mutation Taster		=3/97	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: rs863224974; hg19: chrX-70443601; COSMIC: COSV108896205;