rs1003232768

Variant names:

• chrX-71223179-T-C
• rs1003232768
• ENST00000870749.1:c.-529T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-71223179-T-C
• chrX-71223179-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PS3 PM2 PP5 BP4

The NM_001097642.3(GJB1):​c.-16-513T>C variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000776744: Studies have shown that this variant alters GJB1 gene expression (PMID:23827825).".

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_001097642.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.67
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000776744: Studies have shown that this variant alters GJB1 gene expression (PMID: 23827825).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71223179-T-C is Pathogenic according to our data. Variant chrX-71223179-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 543921.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001097642.3. 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_001097642.3		c.-16-513T>C		intron	N/A	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.-17+413T>C		intron	N/A	NP_001427699.1
	GJB1	NM_000166.6	MANE Select	c.-173T>C		upstream_gene	N/A	NP_000157.1	P08034

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000870749.1		c.-529T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000540808.1
	GJB1	ENST00000870756.1		c.-529T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000540815.1
	GJB1	ENST00000870749.1		c.-529T>C		5_prime_UTR	Exon 2 of 2	ENSP00000540808.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Benign	0.85
PhyloP100		6.7
PromoterAI		-0.0052	Neutral
Mutation Taster		=4/96	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: rs1003232768; hg19: chrX-70443029;