rs41267501

Variant names:

• chr1-201061931-A-G
• rs41267501
• NM_000069.3:c.3053+13T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000069.3(CACNA1S):​c.3053+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,082 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 33)
  • Exomes 𝑓: 0.017 (278 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.979
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 1-201061931-A-G is Benign according to our data. Variant chr1-201061931-A-G is described in ClinVar as Benign. ClinVar VariationId is 254824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0134 (2038/152350) while in subpopulation SAS AF = 0.0377 (182/4826). AF 95% confidence interval is 0.0332. There are 19 homozygotes in GnomAd4. There are 1050 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 SD,AD,AR gene

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.3053+13T>C		intron	N/A	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.3053+13T>C		intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.3053+13T>C		intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.2993+13T>C		intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2039 AN: 152232 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0178 AC: 4483 AN: 251250 AF XY: 0.0195

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00796

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0170 AC: 24836 AN: 1461732 Hom.: 278 Cov.: 33 AF XY: 0.0179 AC XY: 13019 AN XY: 727180

African (AFR) AF: 0.00290 AC: 97 AN: 33478

American (AMR) AF: 0.00861 AC: 385 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 611 AN: 26134

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0360 AC: 3102 AN: 86254

European-Finnish (FIN) AF: 0.0231 AC: 1231 AN: 53366

Middle Eastern (MID) AF: 0.0411 AC: 237 AN: 5768

European-Non Finnish (NFE) AF: 0.0163 AC: 18123 AN: 1111924

Other (OTH) AF: 0.0172 AC: 1037 AN: 60390

GnomAD4 genome AF: 0.0134 AC: 2038 AN: 152350 Hom.: 19 Cov.: 33 AF XY: 0.0141 AC XY: 1050 AN XY: 74494

African (AFR) AF: 0.00291 AC: 121 AN: 41588

American (AMR) AF: 0.0125 AC: 192 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0377 AC: 182 AN: 4826

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10624

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0167 AC: 1137 AN: 68024

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.0145 Hom.: 4

Bravo AF: 0.0117

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	not provided (2)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.1
DANN	Benign	0.29
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -30

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

Other links and lift over

dbSNP: rs41267501; hg19: chr1-201031059; COSMIC: COSV107453886;