rs7415038

Variant names:

• chr1-201069559-A-G
• rs7415038
• NM_000069.3:c.2403T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.2403T>C​(p.Phe801Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.419 in 1,570,430 control chromosomes in the GnomAD database, including 147,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14607 hom., cov: 32)
  • Exomes 𝑓: 0.42 (133302 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.86
• Publications: 18 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 18

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

  Inheritance: SD, AD, AR Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-201069559-A-G is Benign according to our data. Variant chr1-201069559-A-G is described in ClinVar as Benign. ClinVar VariationId is 254814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.2403T>C	p.Phe801Phe	synonymous	Exon 18 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.2403T>C	p.Phe801Phe	synonymous	Exon 18 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.2403T>C	p.Phe801Phe	synonymous	Exon 18 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.2403T>C	p.Phe801Phe	synonymous	Exon 18 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63950 AN: 151872 Hom.: 14602 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.388

GnomAD2 exomes AF: 0.333 AC: 59753 AN: 179650 AF XY: 0.329

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.00295

Gnomad FIN exome AF: 0.292

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.419 AC: 593924 AN: 1418440 Hom.: 133302 Cov.: 42 AF XY: 0.411 AC XY: 288123 AN XY: 700866

African (AFR) AF: 0.535 AC: 17684 AN: 33046

American (AMR) AF: 0.230 AC: 8349 AN: 36358

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 10250 AN: 25276

East Asian (EAS) AF: 0.00159 AC: 61 AN: 38310

South Asian (SAS) AF: 0.181 AC: 14622 AN: 80644

European-Finnish (FIN) AF: 0.302 AC: 15297 AN: 50658

Middle Eastern (MID) AF: 0.307 AC: 1754 AN: 5706

European-Non Finnish (NFE) AF: 0.461 AC: 502590 AN: 1089464

Other (OTH) AF: 0.395 AC: 23317 AN: 58978

GnomAD4 genome AF: 0.421 AC: 63985 AN: 151990 Hom.: 14607 Cov.: 32 AF XY: 0.405 AC XY: 30078 AN XY: 74314

African (AFR) AF: 0.526 AC: 21782 AN: 41434

American (AMR) AF: 0.336 AC: 5130 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1419 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5166

South Asian (SAS) AF: 0.171 AC: 825 AN: 4820

European-Finnish (FIN) AF: 0.283 AC: 2997 AN: 10574

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.448 AC: 30446 AN: 67928

Other (OTH) AF: 0.384 AC: 811 AN: 2112

Alfa AF: 0.438 Hom.: 15852

Bravo AF: 0.431

Asia WGS AF: 0.121 AC: 425 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	Malignant hyperthermia, susceptibility to, 5 (2)
-	-	2	not provided (2)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Benign	0.74
PhyloP100		4.9
Mutation Taster		=67/33	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7415038; hg19: chr1-201038687; COSMIC: COSV62939654;