rs556751671

Positions:

• chr1-201112247-C-A
• chr1-201112247-C-G
• chr1-201112247-C-T

Variant summary

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

The NM_000069.3(CACNA1S):​c.93G>T​(p.Leu31Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,044 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L31L) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07

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, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.93G>T	p.Leu31Phe	missense_variant	1/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.93G>T	p.Leu31Phe	missense_variant	1/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.93G>T	p.Leu31Phe	missense_variant	1/44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74264

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.55
Sift	Benign	0.053	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.79
MutPred		0.45		Loss of disorder (P = 0.1739);Loss of disorder (P = 0.1739);
MVP		0.83
MPC		0.55
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.29
gMVP		0.78

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: rs556751671; hg19: chr1-201081375;