rs145517198

chr7-143320678-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000083.3(CLCN1):c.316C>G(p.Leu106Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,613,256 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00028 (6 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.33

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007871032).
• BP6: Variant 7-143320678-C-G is Benign according to our data. Variant chr7-143320678-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 359096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143320678-C-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.316C>G	p.Leu106Val	missense_variant	3/23	ENST00000343257.7
CLCN1	NR_046453.2	n.418C>G		non_coding_transcript_exon_variant	3/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.316C>G	p.Leu106Val	missense_variant	3/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6	c.85C>G	p.Leu29Val	missense_variant, NMD_transcript_variant	2/23	1
CLCN1	ENST00000650516.2	c.316C>G	p.Leu106Val	missense_variant	3/23			A2

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 151704 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000526

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: 0.0000147

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000736 AC: 185 AN: 251486 Hom.: 0 AF XY: 0.000589 AC XY: 80 AN XY: 135916

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000283 AC: 413 AN: 1461434 Hom.: 6 Cov.: 32 AF XY: 0.000261 AC XY: 190 AN XY: 727056

Gnomad4 AFR exome AF: 0.0107

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00282 AC: 428 AN: 151822 Hom.: 2 Cov.: 30 AF XY: 0.00275 AC XY: 204 AN XY: 74162

Gnomad4 AFR AF: 0.00996

Gnomad4 AMR AF: 0.000525

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000499 Hom.: 0

Bravo AF: 0.00360

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00101 AC: 122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Batten-Turner congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	1.8
Dann	Benign	0.56
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.35	T
Polyphen		0.0020	.;B
Vest4		0.077
MVP		0.69
MPC		0.19
ClinPred		0.0042	T
GERP RS		1.9
Varity_R		0.042
gMVP		0.24

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: rs145517198; hg19: chr7-143017771; COSMIC: COSV58368261; COSMIC: COSV58368261;