rs770392085

Positions:

• chr3-184358248-T-C
• chr3-184358248-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004366.6(CLCN2):​c.415A>G​(p.Thr139Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16

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]

CLCN2 (HGNC:):

ACMG classification

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=0.41492188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN2	NM_004366.6	c.415A>G	p.Thr139Ala	missense_variant	4/24	ENST00000265593.9	NP_004357.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9	c.415A>G	p.Thr139Ala	missense_variant	4/24	1	NM_004366.6	ENSP00000265593.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251430 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;.;.;.;T
Eigen	Benign	0.097
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.8	L;L;.;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N;N;N;.
REVEL	Uncertain	0.64
Sift	Benign	0.23	T;T;T;T;.
Sift4G	Benign	0.56	T;T;T;T;.
Polyphen		0.70	P;P;.;.;.
Vest4		0.85
MutPred		0.41		Loss of glycosylation at T139 (P = 0.2708);Loss of glycosylation at T139 (P = 0.2708);.;Loss of glycosylation at T139 (P = 0.2708);.;
MVP		0.93
MPC		0.39
ClinPred		0.45	T
GERP RS		4.1
Varity_R		0.19
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs770392085; hg19: chr3-184076036;