rs879253995

Variant names:

• chrX-71224083-C-T
• rs879253995
• NM_000166.6:c.376C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1 PP2 PP3_Moderate PP5 BS2

The NM_000166.6(GJB1):​c.376C>T​(p.His126Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,094,628 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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). Synonymous variant affecting the same amino acid position (i.e. H126H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.82
• Publications: 4 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 2 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 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 X-linked progressive cerebellar ataxia, Charcot-Marie-Tooth disease X-linked dominant 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant X-71224083-C-T is Pathogenic according to our data. Variant chrX-71224083-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245904.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.376C>T	p.His126Tyr	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.376C>T	p.His126Tyr	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.376C>T	p.His126Tyr	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.376C>T	p.His126Tyr	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.376C>T	p.His126Tyr	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.376C>T	p.His126Tyr	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1094628 Hom.: 0 Cov.: 32 AF XY: 0.00000555 AC XY: 2 AN XY: 360340

African (AFR) AF: 0.00 AC: 0 AN: 26367

American (AMR) AF: 0.00 AC: 0 AN: 34933

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19208

East Asian (EAS) AF: 0.00 AC: 0 AN: 30143

South Asian (SAS) AF: 0.00 AC: 0 AN: 53321

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40319

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00000714 AC: 6 AN: 840262

Other (OTH) AF: 0.00 AC: 0 AN: 45952

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	0.17
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	0.90	L
PhyloP100		3.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.67
Sift	Benign	0.085	T
Sift4G	Benign	0.11	T
Polyphen		0.83	P
Vest4		0.21
MutPred		0.79		Loss of disorder (P = 0.0277)
MVP		0.96
MPC		0.98
ClinPred		0.55	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.92
Mutation Taster		=12/88	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: rs879253995; hg19: chrX-70443933;