rs146160029

Positions:

• chr7-143316298-A-C

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.86A>C​(p.His29Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00374 in 1,613,774 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (13 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.94

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=0.015843928).
• BP6: Variant 7-143316298-A-C is Benign according to our data. Variant chr7-143316298-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 359091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143316298-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.86A>C	p.His29Pro	missense_variant	1/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.188A>C		non_coding_transcript_exon_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.86A>C	p.His29Pro	missense_variant	1/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000650516.2	c.86A>C	p.His29Pro	missense_variant	1/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152016 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00252 AC: 631 AN: 250872 Hom.: 2 AF XY: 0.00267 AC XY: 362 AN XY: 135638

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00456

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00389 AC: 5680 AN: 1461640 Hom.: 13 Cov.: 32 AF XY: 0.00382 AC XY: 2776 AN XY: 727156

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.000394

Gnomad4 NFE exome AF: 0.00466

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152134 Hom.: 2 Cov.: 32 AF XY: 0.00219 AC XY: 163 AN XY: 74390

Gnomad4 AFR AF: 0.000675

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00438

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00368 Hom.: 2

Bravo AF: 0.00220

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00246 AC: 298

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2020	This variant is associated with the following publications: (PMID: 24349310, 32117024) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CLCN1: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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.86A>C (p.(His29Pro)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita. No other Pathogenic or Likely pathogenic variants were found in this individual. This change 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 the disease. Variant c.86A>C was reported in the HGDM database (CM1313396) in cis with another disease-causing variant. It has been published in PMID: 24349310, found in a patient with AR Becker disease, who carried also two other Pathogeniec/Likely pathogenic CLCN1 variants. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 19, 2019

- -

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2020

This variant is classified as likely 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.71	T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.97	.;L
MutationTaster	Benign	0.87	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	.;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.011	.;D
Sift4G	Benign	0.072	.;T
Polyphen		0.97	.;D
Vest4		0.59
MVP		0.96
MPC		0.75
ClinPred		0.082	T
GERP RS		4.0
Varity_R		0.36
gMVP		0.67

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: rs146160029; hg19: chr7-143013391;