Variant X-155299128-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001289.6(CLIC2):c.75G>C(p.Glu25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,198,587 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

CLIC2
NM_001289.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.160

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:

CLIC2 (HGNC:):

CLIC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.28658727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLIC2	NM_001289.6 linkuse as main transcript	c.75G>C	p.Glu25Asp	missense_variant	2/6	ENST00000369449.7	NP_001280.3	O15247

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLIC2	ENST00000369449.7 linkuse as main transcript	c.75G>C	p.Glu25Asp	missense_variant	2/6	1	NM_001289.6	ENSP00000358460.2	O15247
CLIC2	ENST00000321926.4 linkuse as main transcript	c.75G>C	p.Glu25Asp	missense_variant	2/4	3		ENSP00000318558.4	A6PVS0
CLIC2	ENST00000465553.5 linkuse as main transcript	n.190G>C		non_coding_transcript_exon_variant	2/7	3
CLIC2	ENST00000491205.1 linkuse as main transcript	n.129G>C		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111471

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33667

show subpopulations

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

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182932

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67448

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1087116

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

352908

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000240

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111471

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33667

show subpopulations

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

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.75G>C (p.E25D) alteration is located in exon 2 (coding exon 2) of the CLIC2 gene. This alteration results from a G to C substitution at nucleotide position 75, causing the glutamic acid (E) at amino acid position 25 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.12

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

0.93

P;.

Vest4

0.57

MutPred

0.38

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.52

MPC

1.4

ClinPred

0.79

GERP RS

2.1

Varity_R

0.88

gMVP

0.54

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over