X-155279277-T-C

Position:

• chrX-155279277-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001289.6(CLIC2):​c.454A>G​(p.Thr152Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,259 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T152N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CLIC2 NM_001289.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30002183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC2	NM_001289.6	c.454A>G	p.Thr152Ala	missense_variant	5/6	ENST00000369449.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC2	ENST00000369449.7	c.454A>G	p.Thr152Ala	missense_variant	5/6	1	NM_001289.6	P1
CLIC2	ENST00000321926.4	c.328A>G	p.Thr110Ala	missense_variant	4/4	3
CLIC2	ENST00000465553.5	n.569A>G		non_coding_transcript_exon_variant	5/7	3
CLIC2	ENST00000491205.1	n.508A>G		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183107 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67629

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 9.12e-7 AC: 1 AN: 1096259 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361651

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 03, 2022

Variant summary: CLIC2 c.454A>G (p.Thr152Ala) results in a non-conservative amino acid change located in the Glutathione S-transferase, C-terminal-like (IPR010987) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183107 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.454A>G in individuals affected with X-Linked Intellectual Disability-Cardiomegaly Heart Failure Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.66	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.24
Sift	Benign	0.21	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.049	B;.
Vest4		0.19
MutPred		0.31		Loss of phosphorylation at T152 (P = 0.0522);.;
MVP		0.98
MPC		0.60
ClinPred		0.30	T
GERP RS		4.5
Varity_R		0.36
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557316156; hg19: chrX-154508566;