dbSNP rs782547045: CLIC2:p.Ala131Val (chrX-155279970-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001289.6(CLIC2):c.392C>T(p.Ala131Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000893 in 111,973 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. A131E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Consequence

CLIC2
NM_001289.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.55

Variant links:

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]

CLIC2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC2	NM_001289.6 link	c.392C>T	p.Ala131Val	missense_variant	Exon 4 of 6	ENST00000369449.7	NP_001280.3	O15247

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLIC2	ENST00000369449.7 link	c.392C>T	p.Ala131Val	missense_variant	Exon 4 of 6	1	NM_001289.6	ENSP00000358460.2	O15247
CLIC2	ENST00000321926.4 link	c.266C>T	p.Ala89Val	missense_variant	Exon 3 of 4	3		ENSP00000318558.4	A6PVS0
CLIC2	ENST00000465553.5 link	n.507C>T		non_coding_transcript_exon_variant	Exon 4 of 7	3
CLIC2	ENST00000491205.1 link	n.446C>T		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111973

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34133

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111973

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34133

show subpopulations

Gnomad4 AFR

AF:

0.0000325

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.084

T;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.65

T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.6

D;N

REVEL

Uncertain

0.47

Sift

Benign

0.27

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.18

B;.

Vest4

0.25

MutPred

0.33

Gain of helix (P = 0.062);.;

MVP

0.99

MPC

0.89

ClinPred

0.94

GERP RS

4.7

Varity_R

0.65

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over