X-155279971-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.86
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22750565).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLIC2NM_001289.6 linkc.391G>A p.Ala131Thr missense_variant 4/6 ENST00000369449.7 NP_001280.3 O15247

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLIC2ENST00000369449.7 linkc.391G>A p.Ala131Thr missense_variant 4/61 NM_001289.6 ENSP00000358460.2 O15247
CLIC2ENST00000321926.4 linkc.265G>A p.Ala89Thr missense_variant 3/43 ENSP00000318558.4 A6PVS0
CLIC2ENST00000465553.5 linkn.506G>A non_coding_transcript_exon_variant 4/73
CLIC2ENST00000491205.1 linkn.445G>A non_coding_transcript_exon_variant 5/62

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1067054
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
337530
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

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 submitterclinical testingAmbry GeneticsJul 10, 2024The c.391G>A (p.A131T) alteration is located in exon 4 (coding exon 4) of the CLIC2 gene. This alteration results from a G to A substitution at nucleotide position 391, causing the alanine (A) at amino acid position 131 to be replaced by a threonine (T). 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
Benign
0.094
BayesDel_addAF
Benign
-0.062
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
14
DANN
Benign
0.91
DEOGEN2
Benign
0.076
T;T
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.65
T;T
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.23
T;T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.26
Sift
Benign
0.57
T;T
Sift4G
Benign
0.57
T;T
Polyphen
0.0
B;.
Vest4
0.13
MutPred
0.35
Gain of phosphorylation at A131 (P = 0.0545);.;
MVP
1.0
MPC
0.58
ClinPred
0.17
T
GERP RS
3.8
Varity_R
0.34
gMVP
0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-154509260; API