NM_000069.3:c.1935C>A

Variant names:

• chr1-201075508-G-T
• NM_000069.3:c.1935C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000069.3(CACNA1S):​c.1935C>A​(p.Phe645Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,906 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. Synonymous variant affecting the same amino acid position (i.e. F645F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.1935C>A	p.Phe645Leu	missense_variant	Exon 13 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.1935C>A	p.Phe645Leu	missense_variant	Exon 13 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1935C>A	p.Phe645Leu	missense_variant	Exon 13 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460906 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 726760

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.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;D
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.9	.;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		1.0	.;D
Vest4		0.79
MutPred		0.56		Gain of catalytic residue at F645 (P = 0.1797);Gain of catalytic residue at F645 (P = 0.1797);
MVP		0.83
MPC		0.53
ClinPred		1.0	D
GERP RS		-3.9
Varity_R		0.73
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.42		Position offset: -13

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: chr1-201044636;