rs41276054

Variant names:

• chr7-143332781-G-A
• rs41276054
• NM_000083.3:c.1309G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS2

The NM_000083.3(CLCN1):​c.1309G>A​(p.Ala437Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,042 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A437V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0093 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (159 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.259
• Publications: 10 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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000083.3
• 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=0.0034332275).
• BP6: Variant 7-143332781-G-A is Benign according to our data. Variant chr7-143332781-G-A is described in ClinVar as Benign. ClinVar VariationId is 359109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

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.1309G>A	p.Ala437Thr	missense	Exon 12 of 23	NP_000074.3
	CLCN1	NR_046453.2		n.1356+278G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.1309G>A	p.Ala437Thr	missense	Exon 12 of 23	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.*594G>A		non_coding_transcript_exon	Exon 12 of 23	ENSP00000395949.2
	CLCN1	ENST00000432192.6	TSL:1	n.*594G>A		3_prime_UTR	Exon 12 of 23	ENSP00000395949.2

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1414 AN: 152132 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0109 AC: 2746 AN: 251460 AF XY: 0.0112

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00757

Gnomad ASJ exome AF: 0.0527

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00457

Gnomad NFE exome AF: 0.0133

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0124 AC: 18174 AN: 1461792 Hom.: 159 Cov.: 32 AF XY: 0.0123 AC XY: 8954 AN XY: 727192

African (AFR) AF: 0.00236 AC: 79 AN: 33480

American (AMR) AF: 0.00863 AC: 386 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0506 AC: 1322 AN: 26136

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

South Asian (SAS) AF: 0.00653 AC: 563 AN: 86250

European-Finnish (FIN) AF: 0.00464 AC: 248 AN: 53420

Middle Eastern (MID) AF: 0.00972 AC: 56 AN: 5764

European-Non Finnish (NFE) AF: 0.0132 AC: 14674 AN: 1111936

Other (OTH) AF: 0.0140 AC: 846 AN: 60384

GnomAD4 genome AF: 0.00929 AC: 1415 AN: 152250 Hom.: 12 Cov.: 32 AF XY: 0.00875 AC XY: 651 AN XY: 74420

African (AFR) AF: 0.00294 AC: 122 AN: 41558

American (AMR) AF: 0.0114 AC: 174 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 193 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4818

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 814 AN: 68014

Other (OTH) AF: 0.0128 AC: 27 AN: 2110

Alfa AF: 0.0124 Hom.: 57

Bravo AF: 0.00999

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.0111 AC: 1346

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0155

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Batten-Turner congenital myopathy (1)
-	-	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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.030
DANN	Benign	0.73
DEOGEN2	Benign	0.34	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.59	N
PhyloP100		-0.26
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.21
Sift	Benign	0.57	T
Sift4G	Benign	0.65	T
Polyphen		0.0020	B
Vest4		0.11
MPC		0.18
ClinPred		0.0024	T
GERP RS		-11
Varity_R		0.045
gMVP		0.49
Mutation Taster		=95/5	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: rs41276054; hg19: chr7-143029874; COSMIC: COSV99070811; COSMIC: COSV99070811;