rs201855153

Variant names:

• chr7-143346668-G-A
• rs201855153
• NM_000083.3:c.2364+10G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000083.3(CLCN1):​c.2364+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,607,918 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CLCN1 NM_000083.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0970
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• myotonia congenita, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myotonia congenita, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Thomsen and Becker disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-143346668-G-A is Benign according to our data. Variant chr7-143346668-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 359123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000083.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.2364+10G>A		intron	N/A	NP_000074.3
	CLCN1	NR_046453.2		n.2319+10G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.2364+10G>A		intron	N/A	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.*1649+10G>A		intron	N/A	ENSP00000395949.2
	CLCN1	ENST00000650516.2		c.2364+10G>A		intron	N/A	ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.000999 AC: 152 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000806 AC: 202 AN: 250484 AF XY: 0.000879

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00130 AC: 1897 AN: 1455606 Hom.: 2 Cov.: 31 AF XY: 0.00133 AC XY: 961 AN XY: 724654

African (AFR) AF: 0.000120 AC: 4 AN: 33360

American (AMR) AF: 0.000470 AC: 21 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00118 AC: 102 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00154 AC: 1703 AN: 1106968

Other (OTH) AF: 0.00110 AC: 66 AN: 60236

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74472

African (AFR) AF: 0.000385 AC: 16 AN: 41582

American (AMR) AF: 0.00124 AC: 19 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Batten-Turner congenital myopathy (1)
-	-	1	CLCN1-related disorder (1)
-	-	1	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.9
DANN	Benign	0.62
PhyloP100		-0.097
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201855153; hg19: chr7-143043761;