chrX-71224214-C-A

Variant names:

• chrX-71224214-C-A
• rs373334326
• NM_000166.6:c.507C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000166.6(GJB1):​c.507C>A​(p.Asp169Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D169V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203
• Publications: 2 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 3 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13106209).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.507C>A	p.Asp169Glu	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.507C>A	p.Asp169Glu	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.507C>A	p.Asp169Glu	missense_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.507C>A	p.Asp169Glu	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1094008 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 360296

African (AFR) AF: 0.00 AC: 0 AN: 26366

American (AMR) AF: 0.00 AC: 0 AN: 35004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19305

East Asian (EAS) AF: 0.00 AC: 0 AN: 30146

South Asian (SAS) AF: 0.00 AC: 0 AN: 53648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841060

Other (OTH) AF: 0.00 AC: 0 AN: 46002

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.0
DANN	Benign	0.83
DEOGEN2	Uncertain	0.73	D;D;D;D;D
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.75	.;.;.;.;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.38	N;N;N;N;N
PhyloP100		-0.20
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.55	N;.;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.46	T;.;T;.;T
Sift4G	Benign	0.55	T;.;T;.;T
Polyphen		0.0090	B;B;B;B;B
Vest4		0.078
MutPred		0.23		Gain of ubiquitination at K167 (P = 0.2244);Gain of ubiquitination at K167 (P = 0.2244);Gain of ubiquitination at K167 (P = 0.2244);Gain of ubiquitination at K167 (P = 0.2244);Gain of ubiquitination at K167 (P = 0.2244);
MVP		0.55
MPC		0.76
ClinPred		0.19	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.89
Mutation Taster		=88/12	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: rs373334326; hg19: chrX-70444064;