rs863225254
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004366.6(CLCN2):c.1397G>A(p.Gly466Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 29)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
CLCN2
NM_004366.6 missense, splice_region
NM_004366.6 missense, splice_region
Scores
16
2
1
Splicing: ADA: 0.7589
1
1
Clinical Significance
Conservation
PhyloP100: 7.83
Genes affected
CLCN2 (HGNC:2020): (chloride voltage-gated channel 2) This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.982
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN2 | NM_004366.6 | c.1397G>A | p.Gly466Glu | missense_variant, splice_region_variant | 14/24 | ENST00000265593.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN2 | ENST00000265593.9 | c.1397G>A | p.Gly466Glu | missense_variant, splice_region_variant | 14/24 | 1 | NM_004366.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 genomes
?
Cov.:
29
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459672Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726198
GnomAD4 exome
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1
AN:
1459672
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Cov.:
34
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AC XY:
1
AN XY:
726198
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GnomAD4 genome ? Cov.: 29
GnomAD4 genome
?
Cov.:
29
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects CLCN2 function (PMID: 28905383). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 217790). This missense change has been observed in individual(s) with leukodystrophy (PMID: 28905383). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 466 of the CLCN2 protein (p.Gly466Glu). - |
Leukoencephalopathy with mild cerebellar ataxia and white matter edema Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;.
Sift4G
Pathogenic
D;D;D;.
Polyphen
D;.;.;.
Vest4
MutPred
Loss of methylation at R471 (P = 0.1156);.;Loss of methylation at R471 (P = 0.1156);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at