Genetic Variant CLIC2:p.Ala131Thr (chrX-155279971-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001289.6(CLIC2):c.391G>A(p.Ala131Thr) 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. 15/21 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. A131E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CLIC2
NM_001289.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.86

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome
Inheritance: XL, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

CLIC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22750565).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC2	NM_001289.6	MANE Select	c.391G>A	p.Ala131Thr	missense	Exon 4 of 6	NP_001280.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIC2	ENST00000369449.7	TSL:1 MANE Select	c.391G>A	p.Ala131Thr	missense	Exon 4 of 6	ENSP00000358460.2	O15247
CLIC2	ENST00000948941.1		c.496G>A	p.Ala166Thr	missense	Exon 5 of 7	ENSP00000619000.1
CLIC2	ENST00000321926.4	TSL:3	c.265G>A	p.Ala89Thr	missense	Exon 3 of 4	ENSP00000318558.4	A6PVS0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1067054

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

337530

African (AFR)

AF:

0.00

AC:

AN:

25803

American (AMR)

AF:

0.00

AC:

AN:

35163

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19172

East Asian (EAS)

AF:

0.00

AC:

AN:

30058

South Asian (SAS)

AF:

0.00

AC:

AN:

53408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4053

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

813801

Other (OTH)

AF:

0.00

AC:

AN:

45096

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.076

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.4

PhyloP100

1.9

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.8

REVEL

Benign

0.26

Sift

Benign

0.57

Sift4G

Benign

0.57

Polyphen

0.0

Vest4

0.13

MutPred

0.35

Gain of phosphorylation at A131 (P = 0.0545)

MVP

1.0

MPC

0.58

ClinPred

0.17

GERP RS

3.8

Varity_R

0.34

gMVP

0.35

Mutation Taster

=70/30

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over