X-71224406-G-T

Variant names:

• chrX-71224406-G-T
• rs769112084
• NM_000166.6:c.699G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000166.6(GJB1):​c.699G>T​(p.Ser233Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,767 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S233S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: GJB1 NM_000166.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.646
• 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, 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_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=-0.646 with no splicing effect.

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.699G>T	p.Ser233Ser	synonymous	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.699G>T	p.Ser233Ser	synonymous	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.699G>T	p.Ser233Ser	synonymous	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.699G>T	p.Ser233Ser	synonymous	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.699G>T	p.Ser233Ser	synonymous	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.699G>T	p.Ser233Ser	synonymous	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00000561 AC: 1 AN: 178217 AF XY: 0.0000157

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096767 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 362265

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39939

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841683

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.53
DANN	Benign	0.54
PhyloP100		-0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs769112084; hg19: chrX-70444256;