rs149316679

Positions:

chr7-143346197-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_000083.3(CLCN1):c.2230C>A(p.Pro744Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,700 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.09

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058065444).

BP6

Variant 7-143346197-C-A is Benign according to our data. Variant chr7-143346197-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 359121.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.2230C>A	p.Pro744Thr	missense_variant	18/23	ENST00000343257.7
CLCN1	NR_046453.2 linkuse as main transcript	n.2185C>A		non_coding_transcript_exon_variant	17/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.2230C>A	p.Pro744Thr	missense_variant	18/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*1515C>A		3_prime_UTR_variant, NMD_transcript_variant	18/23	1
CLCN1	ENST00000650516.2 linkuse as main transcript	c.2230C>A	p.Pro744Thr	missense_variant	18/23			A2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000255

AC:

AN:

251412

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000246

AC:

360

AN:

1461638

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

199

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000985

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000210

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000145

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000288

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	This variant is associated with the following publications: (PMID: 22649220) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 13, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 15, 2017

- -

Batten-Turner congenital myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.82

M_CAP

Benign

0.060

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.94

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

REVEL

Benign

0.19

Sift

Benign

0.11

Sift4G

Uncertain

0.044

Polyphen

0.24

Vest4

0.26

MVP

0.91

MPC

0.24

ClinPred

0.039

GERP RS

1.4

Varity_R

0.077

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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