rs863224971

Variant names:

• chrX-71223249-C-T
• rs863224971
• NM_000166.6:c.-103C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-71223249-C-T
• chrX-71223249-C-A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The NM_000166.6(GJB1):​c.-103C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000111 in 89,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003919163: This variant was reported to affect an IRES (internal ribosomal entry site) and subsequently the translation of GJB1 by luciferase reporter assays in transgenic mice and transfected cells (previously reported as c.-459C>T and c.-458C>T in the literature, PMID:10931843, 23827825)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom. 0 hem.)
• Consequence: GJB1 NM_000166.6 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 4.40
• Publications: 9 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003919163: This variant was reported to affect an IRES (internal ribosomal entry site) and subsequently the translation of GJB1 by luciferase reporter assays in transgenic mice and transfected cells (previously reported as c.-459C>T and c.-458C>T in the literature, PMID: 10931843, 23827825); SCV000283685: Studies have shown that this variant alters GJB1 gene expression (PMID: 10931843, 23827825).; SCV000255686: Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant significantly affects translation by disrupting an Internal Ribosome Entry Site (IRES) (PMID: 10931843, 23827825, 34089394).; SCV001794187: Published functional studies indicate impaired protein expression (PMID: 10931843, 23827825)
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71223249-C-T is Pathogenic according to our data. Variant chrX-71223249-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39). . Strength limited to SUPPORTING due to the PP5.

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.-103C>T		5_prime_UTR	Exon 1 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.-16-443C>T		intron	N/A	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.-16-443C>T		intron	N/A	NP_001427699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.-103C>T		5_prime_UTR	Exon 1 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000646835.1		c.-103C>T		5_prime_UTR	Exon 3 of 4	ENSP00000494596.1	P08034
	GJB1	ENST00000675609.1		c.-103C>T		5_prime_UTR	Exon 2 of 3	ENSP00000501571.1	P08034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000111 AC: 1 AN: 89798 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22780

African (AFR) AF: 0.00 AC: 0 AN: 3698

American (AMR) AF: 0.00 AC: 0 AN: 4563

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2366

East Asian (EAS) AF: 0.000200 AC: 1 AN: 4994

South Asian (SAS) AF: 0.00 AC: 0 AN: 8218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4289

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 336

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56121

Other (OTH) AF: 0.00 AC: 0 AN: 5213

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Charcot-Marie-Tooth disease X-linked dominant 1 (7)
3	-	-	not provided (3)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth Neuropathy X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.93
PhyloP100		4.4
PromoterAI		-0.19	Neutral
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs863224971; hg19: chrX-70443099;