1-201083270-C-G

Position:

• chr1-201083270-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000069.3(CACNA1S):​c.1285G>C​(p.Val429Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

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.

• PM1: In a repeat II (size 246) in uniprot entity CAC1S_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000069.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28599584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.1285G>C	p.Val429Leu	missense_variant	10/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.1285G>C	p.Val429Leu	missense_variant	10/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1285G>C	p.Val429Leu	missense_variant	10/44	1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.8	.;H
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.090	.;B
Vest4		0.31
MutPred		0.50		Loss of methylation at K432 (P = 0.07);Loss of methylation at K432 (P = 0.07);
MVP		0.87
MPC		0.12
ClinPred		0.97	D
GERP RS		0.47
Varity_R		0.36
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs750807406; hg19: chr1-201052398;