rs1213746899

Variant names:

• chrX-71224004-A-G
• rs1213746899
• NM_000166.6:c.297A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000166.6(GJB1):​c.297A>G​(p.Gln99Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,200,826 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: GJB1 NM_000166.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.68
• 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant X-71224004-A-G is Benign according to our data. Variant chrX-71224004-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447430.
• BP7: Synonymous conserved (PhyloP=1.68 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.297A>G	p.Gln99Gln	synonymous	Exon 2 of 2	NP_000157.1
	GJB1	NM_001097642.3		c.297A>G	p.Gln99Gln	synonymous	Exon 2 of 2	NP_001091111.1
	GJB1	NM_001440770.1		c.297A>G	p.Gln99Gln	synonymous	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.297A>G	p.Gln99Gln	synonymous	Exon 2 of 2	ENSP00000354900.6
	GJB1	ENST00000374029.2	TSL:5	c.297A>G	p.Gln99Gln	synonymous	Exon 2 of 2	ENSP00000363141.1
	GJB1	ENST00000447581.2	TSL:5	c.297A>G	p.Gln99Gln	synonymous	Exon 3 of 3	ENSP00000407223.2

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111379 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000566

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 168170 AF XY: 0.00

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: 0.00000184 AC: 2 AN: 1089447 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 1 AN XY: 355873

African (AFR) AF: 0.00 AC: 0 AN: 26301

American (AMR) AF: 0.00 AC: 0 AN: 34570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19010

East Asian (EAS) AF: 0.00 AC: 0 AN: 30020

South Asian (SAS) AF: 0.00 AC: 0 AN: 52702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4097

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 836792

Other (OTH) AF: 0.00 AC: 0 AN: 45747

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111379 Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1 AN XY: 33575

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

African (AFR) AF: 0.00 AC: 0 AN: 30652

American (AMR) AF: 0.00 AC: 0 AN: 10481

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3517

South Asian (SAS) AF: 0.00 AC: 0 AN: 2652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000566 AC: 3 AN: 52973

Other (OTH) AF: 0.00 AC: 0 AN: 1495

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Charcot-Marie-Tooth Neuropathy X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.0
DANN	Benign	0.23
PhyloP100		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: rs1213746899; hg19: chrX-70443854;