rs147317366

chr7-143321815-G-Achr7-143321815-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000083.3(CLCN1):c.663G>A(p.Ala221=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,614,214 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A221A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (34 hom.)
• Consequence: CLCN1 NM_000083.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.03

Genes affected

CLCN1 (HGNC:2019): (chloride voltage-gated channel 1) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-143321815-G-A is Benign according to our data. Variant chr7-143321815-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 359104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.03 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.663G>A	p.Ala221=	synonymous_variant	5/23	ENST00000343257.7
CLCN1	NR_046453.2	n.765G>A		non_coding_transcript_exon_variant	5/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.663G>A	p.Ala221=	synonymous_variant	5/23	1	NM_000083.3	P4

Frequencies

GnomAD3 genomes AF: 0.00469 AC: 714 AN: 152232 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00517

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00581 AC: 1461 AN: 251338 Hom.: 10 AF XY: 0.00610 AC XY: 829 AN XY: 135864

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00515 AC: 7532 AN: 1461864 Hom.: 34 Cov.: 33 AF XY: 0.00540 AC XY: 3927 AN XY: 727234

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.00459

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152350 Hom.: 4 Cov.: 33 AF XY: 0.00518 AC XY: 386 AN XY: 74492

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.00517

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00412 Hom.: 2

Bravo AF: 0.00368

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	The c.663G>A (p.(Ala221=)) variant was found in a heterozygous state in 2 Slovak patients with Myotonia congenita, both of whom carried 2 other Likely Pathogenic variants. It is a silent variant that has a population frequency not consistent with the disease (gnomAD ExomesVersion: 4.0 frequency f = 0.00515). Interestingly, both mentioned patients also carried heterozygous CLCN1 splicing variant c.2364+2T>C, indicating its inheritance in cis with c.663G>A. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Batten-Turner congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

CLCN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.23
Dann	Benign	0.88

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: rs147317366; hg19: chr7-143018908;