1-201077914-GC-AT

Variant names:

• chr1-201077914-GC-AT
• NM_000069.3:c.1583_1584delGCinsAT
• CACNA1S p.Arg528His

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM2PM5

The NM_000069.3(CACNA1S):c.1583_1584delGCinsAT (p.Arg528His) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.87). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R528C: Pathogenic/Likely_pathogenic (ClinVar VariationId 849085, 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) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Hypokalemic periodic paralysis, type 1 (hokpp1); it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87
• Publications: 0 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: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	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.R528C: Pathogenic/Likely_pathogenic (ClinVar VariationId 849085, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R528S: Uncertain_significance (ClinVar VariationId 4689585, 1 star)

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.1583_1584delGCinsAT p.Arg528His	missense	N/A	Prot: NP_000060.2 UniProt:

CACNA1S NM_000069.3

MANE Select

HGVSc / HGVSpc.1583_1584delGCinsATp.Arg528His

Exon rankN/A

missense

Prot: NP_000060.2UniProt: Q13698

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CACNA1S ENST00000362061.4	TSL:1MANE Select	c.1583_1584delGCinsAT p.Arg528His	missense	N/A	Prot: ENSP00000355192.3 UniProt:
	CACNA1S ENST00000367338.7	TSL:5	c.1583_1584delGCinsAT p.Arg528His	missense	N/A	Prot: ENSP00000356307.3 UniProt:
	CACNA1S ENST00000681874.1		c.1583_1584delGCinsAT p.Arg528His	missense	N/A	Prot: ENSP00000505162.1 UniProt:

CACNA1S ENST00000362061.4

TSL:1MANE Select

HGVSc / HGVSpc.1583_1584delGCinsATp.Arg528His

Exon rankN/A

missense

Prot: ENSP00000355192.3UniProt: Q13698

CACNA1S ENST00000367338.7

TSL:5

HGVSc / HGVSpc.1583_1584delGCinsATp.Arg528His

Exon rankN/A

missense

Prot: ENSP00000356307.3UniProt: B1ALM3

CACNA1S ENST00000681874.1

HGVSc / HGVSpc.1583_1584delGCinsATp.Arg528His

Exon rankN/A

missense

Prot: ENSP00000505162.1UniProt: 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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr1-201047042;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar