rs147493705

Positions:

chr7-143339519-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP4_StrongBP6BS2

The NM_000083.3(CLCN1):c.1480T>C(p.Phe494Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,612,644 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F494S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 8.01

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:

CLCN1 (HGNC:):

CLCN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a transmembrane_region Helical (size 19) in uniprot entity CLCN1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-143339520-T-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.044286817).

BP6

Variant 7-143339519-T-C is Benign according to our data. Variant chr7-143339519-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418134.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

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 linkuse as main transcript	c.1480T>C	p.Phe494Leu	missense_variant	14/23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 linkuse as main transcript	n.1435T>C		non_coding_transcript_exon_variant	13/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.1480T>C	p.Phe494Leu	missense_variant	14/23	1	NM_000083.3	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6 linkuse as main transcript	n.*765T>C		non_coding_transcript_exon_variant	14/23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6 linkuse as main transcript	n.*765T>C		3_prime_UTR_variant	14/23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000650516.2 linkuse as main transcript	c.1480T>C	p.Phe494Leu	missense_variant	14/23			ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000342

AC:

AN:

251454

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00406

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000136

AC:

198

AN:

1460356

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

726588

show subpopulations

Gnomad4 AFR exome

AF:

0.00457

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152288

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00433

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000241

Hom.:

Bravo

AF:

0.00141

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2018

A variant of uncertain significance has been identified in the CLCN1 gene. The F494L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The F494L variant is observed in 37/10402 (0.4%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F494L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense variant at the same residue (F494S) and in nearby residues (A493E/V, R496S, G499R) have been reported in the Human Gene Mutation Database in association with CLCN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 01, 2023

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

Eigen

Benign

0.061

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.044

MetaSVM

Uncertain

-0.0019

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.49

Sift

Benign

0.13

Sift4G

Benign

0.10

Polyphen

0.052

Vest4

0.93

MutPred

0.49

Loss of catalytic residue at F494 (P = 0.0269);

MVP

0.94

MPC

0.40

ClinPred

0.10

GERP RS

5.1

Varity_R

0.71

gMVP

0.86

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