NM_001289.6:c.680A>T

Variant names:

• chrX-155277967-T-A
• rs782118673
• NM_001289.6:c.680A>T

Variant summary

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

The NM_001289.6(CLIC2):​c.680A>T​(p.His227Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,754 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: CLIC2 NM_001289.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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=0.36844623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC2	NM_001289.6	c.680A>T	p.His227Leu	missense_variant	Exon 6 of 6	ENST00000369449.7	NP_001280.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC2	ENST00000369449.7	c.680A>T	p.His227Leu	missense_variant	Exon 6 of 6	1	NM_001289.6	ENSP00000358460.2
CLIC2	ENST00000465553.5	n.*13A>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111754 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33916

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111754 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33916

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.36
Sift	Benign	0.055	T
Sift4G	Benign	0.13	T
Polyphen		0.45	B
Vest4		0.34
MutPred		0.31		Loss of disorder (P = 0.0384);
MVP		0.98
MPC		0.89
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.62
gMVP		0.50

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: rs782118673; hg19: chrX-154507256;