1-201048677-A-G

Variant names:

• chr1-201048677-A-G
• NM_000069.3:c.4346T>C

Variant summary

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

The NM_000069.3(CACNA1S):​c.4346T>C​(p.Val1449Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,114 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. V1449M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.30

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, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.4346T>C	p.Val1449Ala	missense_variant	Exon 36 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.4289T>C	p.Val1430Ala	missense_variant	Exon 35 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.4346T>C	p.Val1449Ala	missense_variant	Exon 36 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443114 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 716440

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.86	.;P
Vest4		0.71
MutPred		0.57		.;Gain of loop (P = 0.1069);
MVP		0.66
MPC		0.41
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.64
gMVP		0.77

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: chr1-201017805;