7-143339519-T-G

Variant names:

• chr7-143339519-T-G
• NM_000083.3:c.1480T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000083.3(CLCN1):​c.1480T>G​(p.Phe494Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F494S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.01

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 7 ACMG points.

• PM1: In a helix (size 18) in uniprot entity CLCN1_HUMAN there are 11 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 chr7-143339520-T-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1480T>G	p.Phe494Val	missense_variant	Exon 14 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1435T>G		non_coding_transcript_exon_variant	Exon 13 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.1480T>G	p.Phe494Val	missense_variant	Exon 14 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*765T>G		non_coding_transcript_exon_variant	Exon 14 of 23	1		ENSP00000395949.2
CLCN1	ENST00000432192.6	n.*765T>G		3_prime_UTR_variant	Exon 14 of 23	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.1480T>G	p.Phe494Val	missense_variant	Exon 14 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460356 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726588

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.013	B
Vest4		0.88
MutPred		0.51		Gain of methylation at R496 (P = 0.3245);
MVP		0.98
MPC		0.80
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.87

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: chr7-143036612;