7-143316192-C-T

Position:

chr7-143316192-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000083.3(CLCN1):c.-21C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,596,896 control chromosomes in the GnomAD database, including 3,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 220 hom., cov: 32)

Exomes 𝑓: 0.062 ( 3325 hom. )

Consequence

CLCN1
NM_000083.3 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.65

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=-0.79).

BP6

Variant 7-143316192-C-T is Benign according to our data. Variant chr7-143316192-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 359088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143316192-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.-21C>T		5_prime_UTR_variant	1/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.82C>T		non_coding_transcript_exon_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.-21C>T		5_prime_UTR_variant	1/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000650516.2 linkuse as main transcript	c.-21C>T		5_prime_UTR_variant	1/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.0456

AC:

6757

AN:

148284

Hom.:

220

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0127

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0224

Gnomad ASJ

AF:

0.0253

Gnomad EAS

AF:

0.000394

Gnomad SAS

AF:

0.0152

Gnomad FIN

AF:

0.0976

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0695

Gnomad OTH

AF:

0.0332

GnomAD3 exomes

AF:

0.0452

AC:

11055

AN:

244560

Hom.:

391

AF XY:

0.0457

AC XY:

6074

AN XY:

132868

show subpopulations

Gnomad AFR exome

AF:

0.0122

Gnomad AMR exome

AF:

0.0164

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0159

Gnomad FIN exome

AF:

0.0934

Gnomad NFE exome

AF:

0.0677

Gnomad OTH exome

AF:

0.0428

GnomAD4 exome

AF:

0.0625

AC:

90486

AN:

1448536

Hom.:

3325

Cov.:

AF XY:

0.0610

AC XY:

43978

AN XY:

721028

show subpopulations

Gnomad4 AFR exome

AF:

0.0103

Gnomad4 AMR exome

AF:

0.0169

Gnomad4 ASJ exome

AF:

0.0257

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0164

Gnomad4 FIN exome

AF:

0.0852

Gnomad4 NFE exome

AF:

0.0722

Gnomad4 OTH exome

AF:

0.0535

GnomAD4 genome

AF:

0.0456

AC:

6758

AN:

148360

Hom.:

220

Cov.:

AF XY:

0.0453

AC XY:

3279

AN XY:

72328

show subpopulations

Gnomad4 AFR

AF:

0.0127

Gnomad4 AMR

AF:

0.0224

Gnomad4 ASJ

AF:

0.0253

Gnomad4 EAS

AF:

0.000395

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.0976

Gnomad4 NFE

AF:

0.0695

Gnomad4 OTH

AF:

0.0328

Alfa

AF:

0.0517

Hom.:

Bravo

AF:

0.0376

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 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 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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Benign:1

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.-21C>T variant was found in 3 patients with myotonia congenita, one of them homozygous. In one of the heterozygous patients, another Likely Pathogenic variant c.2680C>T was present. The main reason for classification in ClinVar is higher than the supposed population frequency (1 - 5 %). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.60

DANN

Benign

0.77

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

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