NM_000166.6:c.658C>G

Variant names:

• chrX-71224365-C-G
• rs104894814
• NM_000166.6:c.658C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_000166.6(GJB1):​c.658C>G​(p.Arg220Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 1,207,684 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.594
• Publications: 26 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

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.658C>G	p.Arg220Gly	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.658C>G	p.Arg220Gly	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.658C>G	p.Arg220Gly	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.658C>G	p.Arg220Gly	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.658C>G	p.Arg220Gly	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.658C>G	p.Arg220Gly	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110878 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1096806 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 362388

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39585

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000832 AC: 7 AN: 841840

Other (OTH) AF: 0.00 AC: 0 AN: 46071

GnomAD4 genome AF: 0.00000902 AC: 1 AN: 110878 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 33080

African (AFR) AF: 0.00 AC: 0 AN: 30435

American (AMR) AF: 0.00 AC: 0 AN: 10432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2581

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5993

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52894

Other (OTH) AF: 0.00 AC: 0 AN: 1483

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Charcot-Marie-Tooth disease (2)
-	1	-	Charcot-Marie-Tooth Neuropathy X (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.59
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.63
Sift	Benign	0.42	T
Sift4G	Benign	0.58	T
Polyphen		0.85	P
Vest4		0.50
MutPred		0.77		Loss of MoRF binding (P = 0.0728)
MVP		1.0
MPC		1.0
ClinPred		0.17	T
GERP RS		2.0
Varity_R		0.16
gMVP		0.94
Mutation Taster		=16/84	disease causing

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: rs104894814; hg19: chrX-70444215;