chr7-143321392-A-G

Variant names:

• chr7-143321392-A-G
• rs111482384
• NM_000083.3:c.461A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000083.3(CLCN1):​c.461A>G​(p.Gln154Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,614,212 control chromosomes in the GnomAD database, including 57 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q154H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.55
• Publications: 6 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 -19 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=0.0039210916).
• BP6: Variant 7-143321392-A-G is Benign according to our data. Variant chr7-143321392-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0097 (1478/152322) while in subpopulation AFR AF = 0.033 (1373/41568). AF 95% confidence interval is 0.0316. There are 33 homozygotes in GnomAd4. There are 681 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.461A>G	p.Gln154Arg	missense	Exon 4 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.563A>G		non_coding_transcript_exon	Exon 4 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.461A>G	p.Gln154Arg	missense	Exon 4 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.227A>G		non_coding_transcript_exon	Exon 3 of 23	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000650516.2		c.461A>G	p.Gln154Arg	missense	Exon 4 of 23	ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1462 AN: 152204 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00256 AC: 644 AN: 251428 AF XY: 0.00180

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00107 AC: 1565 AN: 1461890 Hom.: 24 Cov.: 33 AF XY: 0.000897 AC XY: 652 AN XY: 727246

African (AFR) AF: 0.0358 AC: 1200 AN: 33480

American (AMR) AF: 0.00241 AC: 108 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: 0.000359 AC: 31 AN: 86258

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

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000656 AC: 73 AN: 1112010

Other (OTH) AF: 0.00233 AC: 141 AN: 60396

GnomAD4 genome AF: 0.00970 AC: 1478 AN: 152322 Hom.: 33 Cov.: 32 AF XY: 0.00914 AC XY: 681 AN XY: 74482

African (AFR) AF: 0.0330 AC: 1373 AN: 41568

American (AMR) AF: 0.00470 AC: 72 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00381 Hom.: 19

Bravo AF: 0.0110

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0345 AC: 152

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00313 AC: 380

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Batten-Turner congenital myopathy (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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.3
DANN	Benign	0.33
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.23
Sift	Benign	0.52	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.80
MPC		0.20
ClinPred		0.0016	T
GERP RS		2.6
Varity_R		0.077
gMVP		0.25
Mutation Taster		=94/6	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: rs111482384; hg19: chr7-143018485;