rs78085922

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000083.3(CLCN1):c.2244G>A(p.Leu748=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,444 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 43 hom., cov: 31)

Exomes 𝑓: 0.013 ( 175 hom. )

Consequence

CLCN1
NM_000083.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.89

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 7-143346211-G-A is Benign according to our data. Variant chr7-143346211-G-A is described in ClinVar as [Benign]. Clinvar id is 359122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143346211-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0171 (2608/152086) while in subpopulation AFR AF= 0.0306 (1269/41460). AF 95% confidence interval is 0.0292. There are 43 homozygotes in gnomad4. There are 1215 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.2244G>A	p.Leu748=	synonymous_variant	18/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.2199G>A		non_coding_transcript_exon_variant	17/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.2244G>A	p.Leu748=	synonymous_variant	18/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*1529G>A		3_prime_UTR_variant, NMD_transcript_variant	18/23	1		ENSP00000395949
CLCN1	ENST00000650516.2 linkuse as main transcript	c.2244G>A	p.Leu748=	synonymous_variant	18/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2607

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0134

Gnomad ASJ

AF:

0.0554

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00444

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0130

AC:

3258

AN:

251308

Hom.:

AF XY:

0.0127

AC XY:

1722

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0308

Gnomad AMR exome

AF:

0.00888

Gnomad ASJ exome

AF:

0.0524

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00640

Gnomad FIN exome

AF:

0.00463

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0131

AC:

19081

AN:

1461358

Hom.:

175

Cov.:

AF XY:

0.0128

AC XY:

9338

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0325

Gnomad4 AMR exome

AF:

0.00993

Gnomad4 ASJ exome

AF:

0.0500

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00678

Gnomad4 FIN exome

AF:

0.00465

Gnomad4 NFE exome

AF:

0.0129

Gnomad4 OTH exome

AF:

0.0159

GnomAD4 genome

AF:

0.0171

AC:

2608

AN:

152086

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1215

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0306

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0554

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.00444

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.0197

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0151

EpiControl

AF:

0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 15, 2021	- -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.1

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over