X-155280064-G-A

Variant names:

• chrX-155280064-G-A
• rs782809067
• NM_001289.6:c.298C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001289.6(CLIC2):​c.298C>T​(p.Pro100Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P100T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CLIC2 NM_001289.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.12

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC2	NM_001289.6	c.298C>T	p.Pro100Ser	missense_variant	Exon 4 of 6	ENST00000369449.7	NP_001280.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC2	ENST00000369449.7	c.298C>T	p.Pro100Ser	missense_variant	Exon 4 of 6	1	NM_001289.6	ENSP00000358460.2
CLIC2	ENST00000321926.4	c.172C>T	p.Pro58Ser	missense_variant	Exon 3 of 4	3		ENSP00000318558.4
CLIC2	ENST00000465553.5	n.413C>T		non_coding_transcript_exon_variant	Exon 4 of 7	3
CLIC2	ENST00000491205.1	n.352C>T		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		1.0	D;.
Vest4		0.46
MutPred		0.47		Gain of loop (P = 0.0097);.;
MVP		0.99
MPC		1.5
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.76

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: rs782809067; hg19: chrX-154509353;