rs1212604561

Variant names:

• chr7-143345578-G-A
• rs1212604561
• NM_000083.3:c.1988G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000083.3(CLCN1):​c.1988G>A​(p.Arg663His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000573 in 1,395,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 3 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: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 0.21191 (below the threshold of 3.09). Trascript score misZ: 0.95247 (below the threshold of 3.09). GenCC associations: The gene is linked to myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Thomsen and Becker disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1728467).

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.1988G>A	p.Arg663His	missense	Exon 17 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.1943G>A		non_coding_transcript_exon	Exon 16 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.1988G>A	p.Arg663His	missense	Exon 17 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.*1273G>A		non_coding_transcript_exon	Exon 17 of 23	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000432192.6	TSL:1	n.*1273G>A		3_prime_UTR	Exon 17 of 23	ENSP00000395949.2	H7C0N6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000129 AC: 2 AN: 155580 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000573 AC: 8 AN: 1395666 Hom.: 0 Cov.: 33 AF XY: 0.00000291 AC XY: 2 AN XY: 687682

African (AFR) AF: 0.00 AC: 0 AN: 31542

American (AMR) AF: 0.00 AC: 0 AN: 35636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.000224 AC: 8 AN: 35676

South Asian (SAS) AF: 0.00 AC: 0 AN: 79154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4996

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076896

Other (OTH) AF: 0.00 AC: 0 AN: 57742

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.24
Sift	Benign	0.067	T
Sift4G	Benign	0.097	T
Polyphen		0.0060	B
Vest4		0.094
MutPred		0.49		Loss of MoRF binding (P = 0.0156)
MVP		0.82
MPC		0.23
ClinPred		0.34	T
GERP RS		1.4
Varity_R		0.098
gMVP		0.42
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1212604561; hg19: chr7-143042671; COSMIC: COSV58369738;