NM_000083.3:c.86A>C

Variant names:

• chr7-143316298-A-C
• rs146160029
• NM_000083.3:c.86A>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_000083.3(CLCN1):​c.86A>C​(p.His29Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00374 in 1,613,774 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (13 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.94
• Publications: 14 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 -15 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=0.015843928).
• BP6: Variant 7-143316298-A-C is Benign according to our data. Variant chr7-143316298-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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.86A>C	p.His29Pro	missense	Exon 1 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.188A>C		non_coding_transcript_exon	Exon 1 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.86A>C	p.His29Pro	missense	Exon 1 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000650516.2		c.86A>C	p.His29Pro	missense	Exon 1 of 23	ENSP00000498052.2	A0A3B3IU72
	CLCN1	ENST00000958857.1		c.86A>C	p.His29Pro	missense	Exon 1 of 22	ENSP00000628916.1

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152016 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00252 AC: 631 AN: 250872 AF XY: 0.00267

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00456

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00389 AC: 5680 AN: 1461640 Hom.: 13 Cov.: 32 AF XY: 0.00382 AC XY: 2776 AN XY: 727156

African (AFR) AF: 0.000747 AC: 25 AN: 33476

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000951 AC: 82 AN: 86258

European-Finnish (FIN) AF: 0.000394 AC: 21 AN: 53286

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5766

European-Non Finnish (NFE) AF: 0.00466 AC: 5181 AN: 1111906

Other (OTH) AF: 0.00424 AC: 256 AN: 60390

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152134 Hom.: 2 Cov.: 32 AF XY: 0.00219 AC XY: 163 AN XY: 74390

African (AFR) AF: 0.000675 AC: 28 AN: 41498

American (AMR) AF: 0.000654 AC: 10 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00438 AC: 298 AN: 67988

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.00349 Hom.: 6

Bravo AF: 0.00220

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00246 AC: 298

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00587

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (2)
-	-	2	not specified (2)
-	-	1	Batten-Turner congenital myopathy (1)
-	-	1	CLCN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.97	L
PhyloP100		3.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.011	D
Sift4G	Benign	0.072	T
Polyphen		0.97	D
Vest4		0.59
MVP		0.96
MPC		0.75
ClinPred		0.082	T
GERP RS		4.0
PromoterAI		0.013	Neutral
Varity_R		0.36
gMVP		0.67
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: rs146160029; hg19: chr7-143013391;