NM_001097642.3:c.-16-513T>G

Variant names:

• chrX-71223179-T-G
• rs1003232768
• NM_001097642.3:c.-16-513T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001097642.3(GJB1):​c.-16-513T>G variant causes a intron change. The variant allele was found at a frequency of 0.0000236 in 42,397 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000024 (0 hom. 0 hem.)
• Consequence: GJB1 NM_001097642.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.67
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_001097642.3		c.-16-513T>G		intron	N/A	NP_001091111.1
	GJB1	NM_001440770.1		c.-17+413T>G		intron	N/A	NP_001427699.1
	GJB1	NM_000166.6	MANE Select	c.-173T>G		upstream_gene	N/A	NP_000157.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000374029.2	TSL:5	c.-16-513T>G		intron	N/A	ENSP00000363141.1
	GJB1	ENST00000447581.2	TSL:5	c.-17+413T>G		intron	N/A	ENSP00000407223.2
	GJB1	ENST00000645009.2		c.-16-513T>G		intron	N/A	ENSP00000494142.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000236 AC: 1 AN: 42397 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 9831

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 1812

American (AMR) AF: 0.00 AC: 0 AN: 2895

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 873

East Asian (EAS) AF: 0.00 AC: 0 AN: 2640

South Asian (SAS) AF: 0.00 AC: 0 AN: 3439

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1661

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 143

European-Non Finnish (NFE) AF: 0.0000377 AC: 1 AN: 26553

Other (OTH) AF: 0.00 AC: 0 AN: 2381

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Charcot-Marie-Tooth disease X-linked dominant 1 (1)
-	1	-	Charcot-Marie-Tooth Neuropathy X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Benign	0.86
PhyloP100		6.7
PromoterAI		-0.0071	Neutral
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;