rs375341574

Positions:

• chr7-143350565-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000083.3(CLCN1):​c.2509-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CLCN1 NM_000083.3 splice_region, intron
• Scores: Splicing: ADA: 0.003153
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.784

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 7-143350565-C-T is Benign according to our data. Variant chr7-143350565-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 511052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.2509-3C>T		splice_region_variant, intron_variant		ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.2464-3C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.2509-3C>T		splice_region_variant, intron_variant		1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*1794-3C>T		splice_region_variant, intron_variant		1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.2509-3C>T		splice_region_variant, intron_variant				ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00681

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000469 AC: 118 AN: 251496 Hom.: 0 AF XY: 0.000338 AC XY: 46 AN XY: 135922

Gnomad AFR exome AF: 0.00646

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000209 AC: 306 AN: 1461662 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 120 AN XY: 727154

Gnomad4 AFR exome AF: 0.00801

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74468

Gnomad4 AFR AF: 0.00679

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00230

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2019	This variant is associated with the following publications: (PMID: 26471370) -

CLCN1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs375341574; hg19: chr7-143047658; COSMIC: COSV100578305; COSMIC: COSV100578305;