rs145910245

chr1-201051037-T-Achr1-201051037-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000069.3(CACNA1S):c.4060A>T(p.Thr1354Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,614,210 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1354I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (33 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 3.14

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009345293).
• BP6: Variant 1-201051037-T-A is Benign according to our data. Variant chr1-201051037-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161208.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5, Benign=1}. Variant chr1-201051037-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00335 (511/152342) while in subpopulation NFE AF= 0.00519 (353/68026). AF 95% confidence interval is 0.00474. There are 1 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.4060A>T	p.Thr1354Ser	missense_variant	33/44	ENST00000362061.4
CACNA1S	XM_005245478.4	c.4003A>T	p.Thr1335Ser	missense_variant	32/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.4060A>T	p.Thr1354Ser	missense_variant	33/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00519

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00264 AC: 663 AN: 251492 Hom.: 1 AF XY: 0.00260 AC XY: 353 AN XY: 135920

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00499 AC: 7295 AN: 1461868 Hom.: 33 Cov.: 35 AF XY: 0.00473 AC XY: 3441 AN XY: 727234

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00598

Gnomad4 OTH exome AF: 0.00492

GnomAD4 genome AF: 0.00335 AC: 511 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00323 AC XY: 241 AN XY: 74498

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00519

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00342 Hom.: 0

Bravo AF: 0.00322

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00236 AC: 287

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CACNA1S: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2016	Variant summary: The CACNA1S c.4060A>T (p.Thr1354Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 287/121696 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0037758 (252/66740). This frequency is about 604 times the estimated maximal expected allele frequency of a pathogenic CACNA1S variant (0.0000063), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant was initially considered pathogenic based on a publication showing segregation of the variant in an affected family, absence in 268 control chromosomes, and functional data demonstrating abnormal Ca++ flux (Pirone_2010). Based on this evidence, Lawrence_2013 listed the variant of interest as a reportable incidental finding in exome sequencing cases. However, the high frequency of this variant in the general population puts into question the true pathogenicity of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a VUS until additional evidence becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	This variant is associated with the following publications: (PMID: 32222817, 29193480, 29212769, 27153395, 27181684, 28011884, 20861472, 24784157, 24055113, 25735680, 25637381, 24195946, 26332594, 27147545) -

Malignant hyperthermia, susceptibility to, 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Oct 30, 2020	This sequence change is predicted to replace threonine with serine at codon 1354 of the CACNA1S protein (p.(Thr1354Ser)). The threonine residue is conserved to fish species, which also have a serine residue at codon 1354 (100 vertebrates, UCSC). The variant is located in the extracellular portion of an ion transporter domain. There is a small physicochemical difference between threonine and serine. The variant is present in a large population cohort at a frequency of 0.52% in the European (non-Finnish) population (rs1145910245, gnomAD v3.0). This variant has been reported in a multigenerational family of individuals who were malignant hyperthermia susceptible (PMID: 20861472) and in two unrelated individuals in an Australian cohort, one of which also had a variant in RYR1 (PMID: 25735680). Patch-clamp analyses demonstrate accelerated inward Ca2+ current and increased sensitisation of RYR1 under caffeine exposure in a transfection model. Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predicting benign/neutral effect, 2/6 algorithms predicting deleterious effect). Based on the classification guidelines RMH Modified ACMG Guidelines v1.3.0, this variant is classified as BENIGN. The following criteria are met: BA1, PP1_Moderate. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.4% (252/66740) Europeans. Classified as VUS in 3 papers (7 total papers in HGMD) -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

CACNA1S-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	19
Dann	Benign	0.33
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0093	T;T
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	0.88	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.6	N;N
REVEL	Uncertain	0.57
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.090	.;B
Vest4		0.28
MutPred		0.57		.;Gain of disorder (P = 0.086);
MVP		0.87
MPC		0.093
ClinPred		0.034	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.58

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: rs145910245; hg19: chr1-201020165;