chrX-71224010-AGAG-A

Variant names:

• chrX-71224010-AGAG-A
• rs1555937135
• NM_000166.6:c.304_306delGAG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The ENST00000361726.7(GJB1):​c.304_306delGAG​(p.Glu102del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 ENST00000361726.7 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:2
• Conservation: PhyloP100: 7.34
• Publications: 0 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: Orphanet, PanelApp Australia, 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 7 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000361726.7
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000361726.7. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-71224010-AGAG-A is Pathogenic according to our data. Variant chrX-71224010-AGAG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 477594.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361726.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.304_306delGAG	p.Glu102del	conservative_inframe_deletion	Exon 2 of 2	NP_000157.1
	GJB1	NM_001097642.3		c.304_306delGAG	p.Glu102del	conservative_inframe_deletion	Exon 2 of 2	NP_001091111.1
	GJB1	NM_001440770.1		c.304_306delGAG	p.Glu102del	conservative_inframe_deletion	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.304_306delGAG	p.Glu102del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000354900.6
	GJB1	ENST00000374029.2	TSL:5	c.304_306delGAG	p.Glu102del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000363141.1
	GJB1	ENST00000447581.2	TSL:5	c.304_306delGAG	p.Glu102del	conservative_inframe_deletion	Exon 3 of 3	ENSP00000407223.2

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=34/66	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: rs1555937135; hg19: chrX-70443860;