rs2272252

Variant names:

• chr7-143339244-C-T
• rs2272252
• NM_000083.3:c.1402-9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000083.3(CLCN1):​c.1402-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,578,338 control chromosomes in the GnomAD database, including 136,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15197 hom., cov: 32)
  • Exomes 𝑓: 0.41 (121371 hom.)
• Consequence: CLCN1 NM_000083.3 intron
• Scores: Splicing: ADA: 0.00001508
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.584
• Publications: 11 publications found

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]

CLCN1 Gene-Disease associations (from GenCC):

• myotonia congenita, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myotonia congenita, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Thomsen and Becker disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-143339244-C-T is Benign according to our data. Variant chr7-143339244-C-T is described in ClinVar as Benign. ClinVar VariationId is 359111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000083.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.1402-9C>T		intron	N/A	NP_000074.3
	CLCN1	NR_046453.2		n.1357-9C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.1402-9C>T		intron	N/A	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.*687-9C>T		intron	N/A	ENSP00000395949.2
	CLCN1	ENST00000650516.2		c.1402-9C>T		intron	N/A	ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66598 AN: 151958 Hom.: 15163 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.401 AC: 100807 AN: 251474 AF XY: 0.402

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.259

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.409 AC: 583403 AN: 1426262 Hom.: 121371 Cov.: 29 AF XY: 0.410 AC XY: 291601 AN XY: 711868

African (AFR) AF: 0.561 AC: 18252 AN: 32546

American (AMR) AF: 0.310 AC: 13854 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 12943 AN: 25862

East Asian (EAS) AF: 0.304 AC: 12007 AN: 39554

South Asian (SAS) AF: 0.417 AC: 35602 AN: 85466

European-Finnish (FIN) AF: 0.387 AC: 20671 AN: 53378

Middle Eastern (MID) AF: 0.450 AC: 2571 AN: 5708

European-Non Finnish (NFE) AF: 0.410 AC: 442357 AN: 1079804

Other (OTH) AF: 0.424 AC: 25146 AN: 59256

GnomAD4 genome AF: 0.439 AC: 66688 AN: 152076 Hom.: 15197 Cov.: 32 AF XY: 0.433 AC XY: 32174 AN XY: 74310

African (AFR) AF: 0.560 AC: 23238 AN: 41484

American (AMR) AF: 0.338 AC: 5160 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1780 AN: 3472

East Asian (EAS) AF: 0.271 AC: 1401 AN: 5178

South Asian (SAS) AF: 0.406 AC: 1959 AN: 4820

European-Finnish (FIN) AF: 0.373 AC: 3935 AN: 10554

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27944 AN: 67968

Other (OTH) AF: 0.447 AC: 942 AN: 2108

Alfa AF: 0.430 Hom.: 10060

Bravo AF: 0.441

Asia WGS AF: 0.352 AC: 1230 AN: 3478

EpiCase AF: 0.424

EpiControl AF: 0.426

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 28, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Apr 22, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Batten-Turner congenital myopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myotonia, autosomal dominant form Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myotonia, autosomal recessive form Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.44
PhyloP100		0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs2272252; hg19: chr7-143036337; COSMIC: COSV58371810;