rs115661422

chr3-184359052-G-Achr3-184359052-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004366.6(CLCN2):c.143C>T(p.Pro48Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,346 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P48R) has been classified as Likely benign.

• 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: 0.678

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]

ACMG classification

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=0.11482561).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN2	NM_004366.6	c.143C>T	p.Pro48Leu	missense_variant	2/24	ENST00000265593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN2	ENST00000265593.9	c.143C>T	p.Pro48Leu	missense_variant	2/24	1	NM_004366.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251080 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461346 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726980

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	Benign	0.088
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.13	T;.;.;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.71	N;N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N;N;N;N;.
REVEL	Benign	0.22
Sift	Benign	0.18	T;T;T;T;.
Sift4G	Benign	0.23	T;T;T;T;.
Polyphen		0.0	B;B;.;.;.
Vest4		0.32
MutPred		0.27		Loss of glycosylation at P53 (P = 0.012);Loss of glycosylation at P53 (P = 0.012);Loss of glycosylation at P53 (P = 0.012);Loss of glycosylation at P53 (P = 0.012);.;
MVP		0.74
MPC		0.29
ClinPred		0.095	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.26

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

Other links and lift over

dbSNP: rs115661422; hg19: chr3-184076840;