7-143321815-G-A

Variant names:

• chr7-143321815-G-A
• rs147317366
• NM_000083.3:c.663G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000083.3(CLCN1):​c.663G>A​(p.Ala221Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,614,214 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A221A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (34 hom.)
• Consequence: CLCN1 NM_000083.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.03
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-143321815-G-A is Benign according to our data. Variant chr7-143321815-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.03 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 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.663G>A	p.Ala221Ala	synonymous	Exon 5 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.765G>A		non_coding_transcript_exon	Exon 5 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.663G>A	p.Ala221Ala	synonymous	Exon 5 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.429G>A		non_coding_transcript_exon	Exon 4 of 23	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000455478.6	TSL:1	n.117G>A		non_coding_transcript_exon	Exon 2 of 7	ENSP00000400027.2	H7C1F4

Frequencies

GnomAD3 genomes AF: 0.00469 AC: 714 AN: 152232 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00517

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00581 AC: 1461 AN: 251338 AF XY: 0.00610

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00515 AC: 7532 AN: 1461864 Hom.: 34 Cov.: 33 AF XY: 0.00540 AC XY: 3927 AN XY: 727234

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00177 AC: 79 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 292 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0109 AC: 940 AN: 86256

European-Finnish (FIN) AF: 0.0130 AC: 693 AN: 53418

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5768

European-Non Finnish (NFE) AF: 0.00459 AC: 5100 AN: 1111998

Other (OTH) AF: 0.00565 AC: 341 AN: 60394

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152350 Hom.: 4 Cov.: 33 AF XY: 0.00518 AC XY: 386 AN XY: 74492

African (AFR) AF: 0.000866 AC: 36 AN: 41580

American (AMR) AF: 0.00268 AC: 41 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

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

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.0174 AC: 185 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00517 AC: 352 AN: 68040

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00412 Hom.: 2

Bravo AF: 0.00368

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00610

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.23
DANN	Benign	0.88
PhyloP100		-3.0
Mutation Taster		=100/0	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: rs147317366; hg19: chr7-143018908;