rs80338777

Variant names:

• chr1-201077915-C-A
• rs80338777
• NM_000069.3:c.1583G>T
• CACNA1S p.Arg528Leu

Your query was ambiguous. Multiple possible variants found:

• chr1-201077915-C-A
• chr1-201077915-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingPM5PP3_StrongPP5

The NM_000069.3(CACNA1S):c.1583G>T (p.Arg528Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000198 (AC=29) in the gnomAD database across 1,461,684 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000163. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.87). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R528H: Pathogenic (ClinVar VariationId 17625, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R528S: Uncertain_significance (ClinVar VariationId 4689585, 1 star)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.87
• Publications: 90 publications found

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]

CACNA1S Gene-Disease associations (from GenCC):

• hypokalemic periodic paralysis, type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR, SD, AD Classification: STRONG Submitted by: Genomics England PanelApp, Illumina
• congenital myopathy 18

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000163 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R528H: Pathogenic (ClinVar VariationId 17625, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R528S: Uncertain_significance (ClinVar VariationId 4689585, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000069.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.1583G>T	p.Arg528Leu	missense	Exon 11 of 44	NP_000060.2	Q13698

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.1583G>T	p.Arg528Leu	missense	Exon 11 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.1583G>T	p.Arg528Leu	missense	Exon 11 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.1583G>T	p.Arg528Leu	missense	Exon 11 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.0000119	AC:3	Hom:	AN:251124	Cov:
GnomAD4 exome	AF: 0.0000198	AC:29	Hom:0	AN:1461684	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo)	AF: 0.0000189	AC:5	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000441	AC:1	Hom:0	AN:226764	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
SCHEMA(Schizophrenia)	0.00	0	67846	0.0000150	2	133310

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Malignant hyperthermia, susceptibility to, 5 (2)
1	-	-	CACNA1S-related disorder (1)
1	-	-	Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 (1)
1	-	-	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-9.7
GPN-Star score	N/A	9.7
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	7/93	disease causing
MutationAssessor	Pathogenic	3.4	M
PhyloP100	Pathogenic	7.9
popEVE	Benign	-3.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.94
VESM-3B	Benign	-15

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs80338777;

hg19: chr1-201047043;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar