rs587777879

Variant names:

• chrX-71224497-C-T
• rs587777879
• NM_000166.6:c.790C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-71224497-C-T
• chrX-71224497-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1 PP2 PP3_Moderate BP6 BS2

The NM_000166.6(GJB1):​c.790C>T​(p.Arg264Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,198,038 control chromosomes in the GnomAD database, including 1 homozygotes. There are 8 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000029 (1 hom. 8 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:1
• Conservation: PhyloP100: 2.61
• Publications: 7 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 0 ACMG points.

• PM1: In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 184 pathogenic changes around while only 11 benign (94%) 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 X-linked progressive cerebellar ataxia, Charcot-Marie-Tooth disease X-linked dominant 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• BP6: Variant X-71224497-C-T is Benign according to our data. Variant chrX-71224497-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 155727.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

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.790C>T	p.Arg264Cys	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.790C>T	p.Arg264Cys	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.790C>T	p.Arg264Cys	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.790C>T	p.Arg264Cys	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.790C>T	p.Arg264Cys	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.790C>T	p.Arg264Cys	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111495 Hom.: 0 Cov.: 22

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000571 AC: 9 AN: 157521 AF XY: 0.0000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000244

Gnomad FIN exome AF: 0.0000705

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000247

GnomAD4 exome AF: 0.0000285 AC: 31 AN: 1086543 Hom.: 1 Cov.: 31 AF XY: 0.0000226 AC XY: 8 AN XY: 353907

African (AFR) AF: 0.0000382 AC: 1 AN: 26146

American (AMR) AF: 0.000176 AC: 6 AN: 34110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19158

East Asian (EAS) AF: 0.000168 AC: 5 AN: 29785

South Asian (SAS) AF: 0.00 AC: 0 AN: 52565

European-Finnish (FIN) AF: 0.0000254 AC: 1 AN: 39300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.0000203 AC: 17 AN: 835679

Other (OTH) AF: 0.0000219 AC: 1 AN: 45680

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111495 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33665

African (AFR) AF: 0.00 AC: 0 AN: 30628

American (AMR) AF: 0.00 AC: 0 AN: 10483

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3503

South Asian (SAS) AF: 0.00 AC: 0 AN: 2667

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6023

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53106

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.00000834 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000332 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.69	N
PhyloP100		2.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.64
Sift	Benign	0.044	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.45
MutPred		0.83		Loss of solvent accessibility (P = 0.0404)
MVP		1.0
MPC		1.4
ClinPred		0.080	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.74
Mutation Taster		=46/54	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: rs587777879; hg19: chrX-70444347;