7-143345614-A-G

Variant names:

• chr7-143345614-A-G
• rs768582911
• NM_000083.3:c.2024A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000083.3(CLCN1):​c.2024A>G​(p.Gln675Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q675P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.583
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000083.3
• PM2: Very rare variant in population databases, with high coverage
• 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=0.077584684).

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.2024A>G	p.Gln675Arg	missense	Exon 17 of 23	NP_000074.3
	CLCN1	NR_046453.2		n.1979A>G		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.2024A>G	p.Gln675Arg	missense	Exon 17 of 23	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.*1309A>G		non_coding_transcript_exon	Exon 17 of 23	ENSP00000395949.2
	CLCN1	ENST00000432192.6	TSL:1	n.*1309A>G		3_prime_UTR	Exon 17 of 23	ENSP00000395949.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406340 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 694532

African (AFR) AF: 0.00 AC: 0 AN: 32044

American (AMR) AF: 0.00 AC: 0 AN: 36580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36340

South Asian (SAS) AF: 0.00 AC: 0 AN: 79814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5244

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083646

Other (OTH) AF: 0.00 AC: 0 AN: 58228

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.58
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.18
Sift	Benign	0.50	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.025
MutPred		0.33		Gain of helix (P = 0.005)
MVP		0.80
MPC		0.20
ClinPred		0.11	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.26
Mutation Taster		=83/17	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: rs768582911; hg19: chr7-143042707;