X-155279309-T-C

Variant names:

• chrX-155279309-T-C
• rs2074910042
• NM_001289.6:c.422A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001289.6(CLIC2):​c.422A>G​(p.Lys141Arg) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CLIC2 NM_001289.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165

Genes affected

CLIC2 (HGNC:2063): (chloride intracellular channel 2) This gene encodes a chloride intracellular channel protein. Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. This protein plays a role in inhibiting the function of ryanodine receptor 2. A mutation in this gene is the cause of an X-linked form of cognitive disability. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101968855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC2	NM_001289.6	c.422A>G	p.Lys141Arg	missense_variant	Exon 5 of 6	ENST00000369449.7	NP_001280.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC2	ENST00000369449.7	c.422A>G	p.Lys141Arg	missense_variant	Exon 5 of 6	1	NM_001289.6	ENSP00000358460.2
CLIC2	ENST00000321926.4	c.296A>G	p.Lys99Arg	missense_variant	Exon 4 of 4	3		ENSP00000318558.4
CLIC2	ENST00000465553.5	n.537A>G		non_coding_transcript_exon_variant	Exon 5 of 7	3
CLIC2	ENST00000491205.1	n.476A>G		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 25, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.36	T;T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.015	N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.24
Sift	Benign	0.37	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	B;.
Vest4		0.069
MutPred		0.34		Gain of ubiquitination at K137 (P = 0.0419);.;
MVP		0.93
MPC		0.47
ClinPred		0.083	T
GERP RS		-1.0
Varity_R		0.17
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2074910042; hg19: chrX-154508598;