rs199626569

Variant names:

• chrX-71224204-T-G
• rs199626569
• NM_000166.6:c.497T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1 PM2 PP2 PP3 BP4_Strong

The NM_000166.6(GJB1):​c.497T>G​(p.Val166Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.00016 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 8.02
• Publications: 3 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 2 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.019070834).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.497T>G	p.Val166Gly	missense	Exon 2 of 2	NP_000157.1
	GJB1	NM_001097642.3		c.497T>G	p.Val166Gly	missense	Exon 2 of 2	NP_001091111.1
	GJB1	NM_001440770.1		c.497T>G	p.Val166Gly	missense	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.497T>G	p.Val166Gly	missense	Exon 2 of 2	ENSP00000354900.6
	GJB1	ENST00000374029.2	TSL:5	c.497T>G	p.Val166Gly	missense	Exon 2 of 2	ENSP00000363141.1
	GJB1	ENST00000447581.2	TSL:5	c.497T>G	p.Val166Gly	missense	Exon 3 of 3	ENSP00000407223.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00109 AC: 176 AN: 161923 AF XY: 0.00

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.000833

Gnomad ASJ exome AF: 0.000142

Gnomad EAS exome AF: 0.00320

Gnomad FIN exome AF: 0.000965

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000730

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000164 AC: 178 AN: 1086803 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 356549

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

African (AFR) AF: 0.000422 AC: 11 AN: 26051

American (AMR) AF: 0.00165 AC: 55 AN: 33355

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19122

East Asian (EAS) AF: 0.00143 AC: 42 AN: 29420

South Asian (SAS) AF: 0.0000377 AC: 2 AN: 53039

European-Finnish (FIN) AF: 0.000747 AC: 28 AN: 37466

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4126

European-Non Finnish (NFE) AF: 0.0000358 AC: 30 AN: 838545

Other (OTH) AF: 0.000197 AC: 9 AN: 45679

⚠️ 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.: 21

Alfa AF: 0.0000167 Hom.: 0

ExAC AF: 0.00327 AC: 396

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease Uncertain:1

Oct 28, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.019	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.0
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.57
MVP		0.93
MPC		2.1
ClinPred		0.072	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		1.0
Mutation Taster		=5/95	disease causing

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: rs199626569; hg19: chrX-70444054; COSMIC: COSV106110523; COSMIC: COSV106110523;