rs115661422

Variant names:

• chr3-184359052-G-C
• rs115661422
• NM_004366.6:c.143C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-184359052-G-C
• chr3-184359052-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004366.6(CLCN2):​c.143C>G​(p.Pro48Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,656 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (8 hom.)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.678
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• leukoencephalopathy with mild cerebellar ataxia and white matter edema

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epilepsy, idiopathic generalized, susceptibility to, 11

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial hyperaldosteronism type II

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049925745).
• BP6: Variant 3-184359052-G-C is Benign according to our data. Variant chr3-184359052-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 217768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00567 (864/152310) while in subpopulation AFR AF = 0.0199 (828/41576). AF 95% confidence interval is 0.0188. There are 11 homozygotes in GnomAd4. There are 433 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004366.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	NM_004366.6	MANE Select	c.143C>G	p.Pro48Arg	missense	Exon 2 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.143C>G	p.Pro48Arg	missense	Exon 2 of 24	NP_001164558.1	P51788-3
	CLCN2	NM_001171089.3		c.143C>G	p.Pro48Arg	missense	Exon 2 of 23	NP_001164560.1	P51788-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	ENST00000265593.9	TSL:1 MANE Select	c.143C>G	p.Pro48Arg	missense	Exon 2 of 24	ENSP00000265593.4	P51788-1
	CLCN2	ENST00000344937.11	TSL:1	c.143C>G	p.Pro48Arg	missense	Exon 2 of 24	ENSP00000345056.7	P51788-3
	CLCN2	ENST00000938001.1		c.260C>G	p.Pro87Arg	missense	Exon 3 of 25	ENSP00000608060.1

Frequencies

GnomAD3 genomes AF: 0.00564 AC: 858 AN: 152192 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00153 AC: 385 AN: 251080 AF XY: 0.00105

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000580 AC: 847 AN: 1461346 Hom.: 8 Cov.: 33 AF XY: 0.000459 AC XY: 334 AN XY: 726980

African (AFR) AF: 0.0209 AC: 700 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52878

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112008

Other (OTH) AF: 0.00139 AC: 84 AN: 60394

GnomAD4 genome AF: 0.00567 AC: 864 AN: 152310 Hom.: 11 Cov.: 33 AF XY: 0.00581 AC XY: 433 AN XY: 74470

African (AFR) AF: 0.0199 AC: 828 AN: 41576

American (AMR) AF: 0.00189 AC: 29 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00621

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00177 AC: 215

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	-	Leukoencephalopathy with mild cerebellar ataxia and white matter edema (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.68
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.87	N
REVEL	Benign	0.12
Sift	Benign	0.49	T
Sift4G	Benign	0.59	T
Polyphen		0.022	B
Vest4		0.29
MVP		0.81
MPC		0.30
ClinPred		0.0047	T
GERP RS		2.5
PromoterAI		0.091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.22
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs115661422; hg19: chr3-184076840;