rs73726622

Positions:

• chr7-143345726-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000083.3(CLCN1):​c.2136T>C​(p.Asp712Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,587,048 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (15 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (16 hom.)
• Consequence: CLCN1 NM_000083.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.408

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 7-143345726-T-C is Benign according to our data. Variant chr7-143345726-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 359117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.408 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00845 (1281/151536) while in subpopulation AFR AF= 0.0284 (1175/41320). AF 95% confidence interval is 0.0271. There are 15 homozygotes in gnomad4. There are 600 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.2136T>C	p.Asp712Asp	synonymous_variant	17/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.2091T>C		non_coding_transcript_exon_variant	16/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.2136T>C	p.Asp712Asp	synonymous_variant	17/23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*1421T>C		non_coding_transcript_exon_variant	17/23	1		ENSP00000395949.2
CLCN1	ENST00000432192.6	n.*1421T>C		3_prime_UTR_variant	17/23	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.2136T>C	p.Asp712Asp	synonymous_variant	17/23			ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1280 AN: 151420 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00530

GnomAD3 exomes AF: 0.00262 AC: 526 AN: 200416 Hom.: 3 AF XY: 0.00207 AC XY: 226 AN XY: 109246

Gnomad AFR exome AF: 0.0315

Gnomad AMR exome AF: 0.00424

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000771

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00368

GnomAD4 exome AF: 0.00114 AC: 1633 AN: 1435512 Hom.: 16 Cov.: 33 AF XY: 0.00102 AC XY: 724 AN XY: 711372

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000974

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.000291

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.00845 AC: 1281 AN: 151536 Hom.: 15 Cov.: 31 AF XY: 0.00811 AC XY: 600 AN XY: 73992

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.00459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000310

Gnomad4 OTH AF: 0.00524

Alfa AF: 0.00429 Hom.: 3

Bravo AF: 0.00968

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 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. -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.9
DANN	Benign	0.71

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

Other links and lift over

dbSNP: rs73726622; hg19: chr7-143042819;