rs1325309

Variant names:

• chr1-201110330-T-A
• rs1325309
• NM_000069.3:c.153-61A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.153-61A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,421,418 control chromosomes in the GnomAD database, including 144,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17525 hom., cov: 33)
  • Exomes 𝑓: 0.44 (127380 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.916
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-201110330-T-A is Benign according to our data. Variant chr1-201110330-T-A is described in ClinVar as Benign. ClinVar VariationId is 678214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 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.153-61A>T		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.153-61A>T		intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.153-61A>T		intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.153-61A>T		intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71609 AN: 151986 Hom.: 17499 Cov.: 33

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.490

GnomAD4 exome AF: 0.442 AC: 561395 AN: 1269314 Hom.: 127380 AF XY: 0.444 AC XY: 284369 AN XY: 640632

African (AFR) AF: 0.554 AC: 16623 AN: 30030

American (AMR) AF: 0.577 AC: 25338 AN: 43938

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10305 AN: 24916

East Asian (EAS) AF: 0.822 AC: 31963 AN: 38880

South Asian (SAS) AF: 0.543 AC: 44786 AN: 82510

European-Finnish (FIN) AF: 0.379 AC: 20047 AN: 52868

Middle Eastern (MID) AF: 0.490 AC: 2664 AN: 5440

European-Non Finnish (NFE) AF: 0.411 AC: 384882 AN: 936702

Other (OTH) AF: 0.459 AC: 24787 AN: 54030

GnomAD4 genome AF: 0.471 AC: 71686 AN: 152104 Hom.: 17525 Cov.: 33 AF XY: 0.473 AC XY: 35159 AN XY: 74338

African (AFR) AF: 0.544 AC: 22599 AN: 41514

American (AMR) AF: 0.523 AC: 8001 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1415 AN: 3466

East Asian (EAS) AF: 0.814 AC: 4210 AN: 5170

South Asian (SAS) AF: 0.550 AC: 2649 AN: 4820

European-Finnish (FIN) AF: 0.361 AC: 3818 AN: 10580

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27432 AN: 67958

Other (OTH) AF: 0.491 AC: 1034 AN: 2106

Alfa AF: 0.444 Hom.: 1902

Bravo AF: 0.490

Asia WGS AF: 0.659 AC: 2288 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypokalemic periodic paralysis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.71
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1325309; hg19: chr1-201079458; COSMIC: COSV62942879; COSMIC: COSV62942879;