rs1293789661

Variant summary

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

The NM_004366.6(CLCN2):​c.515G>T​(p.Arg172Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

12
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.89
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLCN2NM_004366.6 linkc.515G>T p.Arg172Leu missense_variant Exon 5 of 24 ENST00000265593.9 NP_004357.3 P51788-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLCN2ENST00000265593.9 linkc.515G>T p.Arg172Leu missense_variant Exon 5 of 24 1 NM_004366.6 ENSP00000265593.4 P51788-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461780
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727176
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D;.;.;.;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D
M_CAP
Pathogenic
0.48
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Uncertain
2.5
M;M;.;M;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.1
D;D;D;D;.
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;D;D;D;.
Sift4G
Uncertain
0.0030
D;D;D;D;.
Polyphen
1.0
D;D;.;.;.
Vest4
0.93
MutPred
0.64
Loss of MoRF binding (P = 0.1277);Loss of MoRF binding (P = 0.1277);.;Loss of MoRF binding (P = 0.1277);.;
MVP
0.96
MPC
1.1
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.85

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: chr3-184075850; API