chr7-143346256-C-T

Position:

chr7-143346256-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000083.3(CLCN1):c.2284+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,590,352 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.017 ( 32 hom., cov: 31)

Exomes 𝑓: 0.025 ( 559 hom. )

Consequence

CLCN1
NM_000083.3 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.001404

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: -0.313

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 7-143346256-C-T is Benign according to our data. Variant chr7-143346256-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252462.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}. Variant chr7-143346256-C-T is described in Lovd as [Benign]. Variant chr7-143346256-C-T is described in Lovd as [Likely_benign]. Variant chr7-143346256-C-T is described in Lovd as [Pathogenic]. Variant chr7-143346256-C-T is described in Lovd as [Pathogenic]. Variant chr7-143346256-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2605/152228) while in subpopulation NFE AF= 0.0281 (1913/68020). AF 95% confidence interval is 0.0271. There are 32 homozygotes in gnomad4. There are 1143 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.2284+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.2239+5C>T		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.2284+5C>T	splice_donor_5th_base_variant, intron_variant	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*1569+5C>T	splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant	1		ENSP00000395949
CLCN1	ENST00000650516.2 linkuse as main transcript	c.2284+5C>T	splice_donor_5th_base_variant, intron_variant			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2605

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00993

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0281

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0178

AC:

4457

AN:

250744

Hom.:

AF XY:

0.0183

AC XY:

2475

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.00524

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.00984

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00879

Gnomad FIN exome

AF:

0.00532

Gnomad NFE exome

AF:

0.0288

Gnomad OTH exome

AF:

0.0198

GnomAD4 exome

AF:

0.0254

AC:

36510

AN:

1438124

Hom.:

559

Cov.:

AF XY:

0.0250

AC XY:

17947

AN XY:

716904

show subpopulations

Gnomad4 AFR exome

AF:

0.00489

Gnomad4 AMR exome

AF:

0.0143

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00922

Gnomad4 FIN exome

AF:

0.00748

Gnomad4 NFE exome

AF:

0.0301

Gnomad4 OTH exome

AF:

0.0207

GnomAD4 genome

AF:

0.0171

AC:

2605

AN:

152228

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1143

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00571

Gnomad4 AMR

AF:

0.0182

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00994

Gnomad4 FIN

AF:

0.00405

Gnomad4 NFE

AF:

0.0281

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0220

Hom.:

Bravo

AF:

0.0175

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0291

EpiControl

AF:

0.0302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2019	This variant is associated with the following publications: (PMID: 24349310, 23739125, 11840191, 24452722, 15786415, 21221019, 22094069, 23152584, 12196568, 27614575, 27884173, 28427807, 15311340, 32117024) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CLCN1: BP4, BS1, BS2 -

Congenital myotonia, autosomal recessive form

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: BP4. -

Batten-Turner congenital myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

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

-0.74

CADD

Benign

5.6

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.018

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