rs1554438432

Variant names:

• chr7-143341957-CCA-C
• rs1554438432
• NM_000083.3:c.1616_1617delCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000083.3(CLCN1):​c.1616_1617delCA​(p.Thr539SerfsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLCN1 NM_000083.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32
• Publications: 0 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-143341957-CCA-C is Pathogenic according to our data. Variant chr7-143341957-CCA-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 447055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.1616_1617delCA	p.Thr539SerfsTer40	frameshift	Exon 15 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.1571_1572delCA		non_coding_transcript_exon	Exon 14 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.1616_1617delCA	p.Thr539SerfsTer40	frameshift	Exon 15 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.*901_*902delCA		non_coding_transcript_exon	Exon 15 of 23	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000432192.6	TSL:1	n.*901_*902delCA		3_prime_UTR	Exon 15 of 23	ENSP00000395949.2	H7C0N6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461634 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1554438432; hg19: chr7-143039050;