rs864622215

Variant names:

• chrX-71224351-G-A
• rs864622215
• NM_000166.6:c.644G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-71224351-G-A
• chrX-71224351-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 6P and 5B. PM1 PM5 PP2 PP5 BP4 BS2

The NM_000166.6(GJB1):​c.644G>A​(p.Arg215Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000073 in 1,096,602 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000073 (0 hom. 6 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.70
• Publications: 8 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000166.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71224350-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 246098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP5: Variant X-71224351-G-A is Pathogenic according to our data. Variant chrX-71224351-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1958026.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3405183). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

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.644G>A	p.Arg215Gln	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.644G>A	p.Arg215Gln	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.644G>A	p.Arg215Gln	missense	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.644G>A	p.Arg215Gln	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.644G>A	p.Arg215Gln	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.644G>A	p.Arg215Gln	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000730 AC: 8 AN: 1096602 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 6 AN XY: 362294

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19355

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.000129 AC: 7 AN: 54059

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39387

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841829

Other (OTH) AF: 0.0000217 AC: 1 AN: 46068

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.63	N
PhyloP100		2.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.36
Sift	Benign	0.044	D
Sift4G	Uncertain	0.060	T
Polyphen		0.058	B
Vest4		0.13
MutPred		0.57		Loss of MoRF binding (P = 0.0237)
MVP		0.91
MPC		0.89
ClinPred		0.80	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.97
Mutation Taster		=55/45	polymorphism

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: rs864622215; hg19: chrX-70444201;