NM_000069.3:c.1452C>T

Variant names:

• chr1-201078046-G-A
• rs144206959
• NM_000069.3:c.1452C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000069.3(CACNA1S):​c.1452C>T​(p.Tyr484Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,614,232 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.554

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-201078046-G-A is Benign according to our data. Variant chr1-201078046-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 254793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201078046-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.554 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000971 (148/152346) while in subpopulation NFE AF= 0.00168 (114/68030). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.1452C>T	p.Tyr484Tyr	synonymous_variant	Exon 11 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.1452C>T	p.Tyr484Tyr	synonymous_variant	Exon 11 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.1452C>T	p.Tyr484Tyr	synonymous_variant	Exon 11 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 148 AN: 152228 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00115 AC: 288 AN: 251488 Hom.: 0 AF XY: 0.00127 AC XY: 172 AN XY: 135918

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000947

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00150 AC: 2191 AN: 1461886 Hom.: 3 Cov.: 35 AF XY: 0.00149 AC XY: 1082 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00178

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000971 AC: 148 AN: 152346 Hom.: 0 Cov.: 30 AF XY: 0.000832 AC XY: 62 AN XY: 74500

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00100

EpiCase AF: 0.00213

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1S: BP4, BP7 -

Hypokalemic periodic paralysis, type 1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 5 Benign:2

Oct 11, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy 18 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary liability to pressure palsies Benign:1

Dec 13, 2019

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.8
DANN	Benign	0.61

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: rs144206959; hg19: chr1-201047174; COSMIC: COSV62942301;