rs80356688

Variant names:

• chr7-143324486-C-G
• NM_000083.3:c.847C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-143324486-C-G
• chr7-143324486-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000083.3(CLCN1):​c.847C>G​(p.Leu283Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L283F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 9) in uniprot entity CLCN1_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000083.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143324486-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.847C>G	p.Leu283Val	missense_variant	Exon 7 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.952C>G		non_coding_transcript_exon_variant	Exon 7 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.847C>G	p.Leu283Val	missense_variant	Exon 7 of 23	1	NM_000083.3	ENSP00000339867.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460948 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726828

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.094
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	-0.045	N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.54
Sift	Benign	0.21	T
Sift4G	Benign	0.26	T
Polyphen		0.022	B
Vest4		0.79
MutPred		0.74		Gain of catalytic residue at L283 (P = 0.1778);
MVP		0.94
MPC		0.26
ClinPred		0.86	D
GERP RS		4.6
Varity_R		0.37
gMVP		0.72

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-143021579;