rs114191482

Variant names:

• chr1-201077036-C-A
• rs114191482
• NM_000069.3:c.1711G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201077036-C-A
• chr1-201077036-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000069.3(CACNA1S):​c.1711G>T​(p.Val571Phe) 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 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V571I) has been classified as Likely benign.

• 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: -0.00300

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000069.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.1711G>T	p.Val571Phe	missense_variant	Exon 12 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.1711G>T	p.Val571Phe	missense_variant	Exon 12 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1711G>T	p.Val571Phe	missense_variant	Exon 12 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 8.99e-7

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	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.47	.;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.51
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.34	.;B
Vest4		0.59
MutPred		0.61		Loss of catalytic residue at V571 (P = 0.031);Loss of catalytic residue at V571 (P = 0.031);
MVP		0.91
MPC		0.45
ClinPred		0.87	D
GERP RS		-2.8
Varity_R		0.25
gMVP		0.80

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: rs114191482; hg19: chr1-201046164;