rs879254047

Variant names:

• chrX-71223335-G-A
• rs879254047
• NM_000166.6:c.-17G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000166.6(GJB1):​c.-17G>A variant causes a splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 splice_region
• Scores: Splicing: ADA: 0.9193
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.58
• 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, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71223335-G-A is Pathogenic according to our data. Variant chrX-71223335-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 246014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47). . 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.-17G>A		splice_region	Exon 1 of 2	NP_000157.1	P08034
	GJB1	NM_000166.6	MANE Select	c.-17G>A		5_prime_UTR	Exon 1 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.-16-357G>A		intron	N/A	NP_001091111.1	P08034

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.-17G>A		splice_region	Exon 1 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.-17G>A		5_prime_UTR	Exon 1 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000646835.1		c.-17G>A		splice_region	Exon 3 of 4	ENSP00000494596.1	P08034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Charcot-Marie-Tooth disease X-linked dominant 1 (3)
2	-	-	not provided (2)
1	-	-	Charcot-Marie-Tooth Neuropathy X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.85
PhyloP100		4.6
PromoterAI		-0.082	Neutral
Mutation Taster		=122/178	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.86
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: rs879254047; hg19: chrX-70443185;