rs113792034

Variant names:

• chr1-201065959-G-A
• rs113792034
• NM_000069.3:c.2746-14C>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.2746-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0406 in 1,571,438 control chromosomes in the GnomAD database, including 1,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (120 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1330 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.848
• 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):

• congenital myopathy 18

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypokalemic periodic paralysis, type 1

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

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

  Inheritance: SD, AR, AD 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=-0.79).
• BP6: Variant 1-201065959-G-A is Benign according to our data. Variant chr1-201065959-G-A is described in ClinVar as Benign. ClinVar VariationId is 254821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0633 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.2746-14C>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.2746-14C>T		intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.2746-14C>T		intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.2686-14C>T		intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5698 AN: 152190 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0559

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0367 AC: 8748 AN: 238478 AF XY: 0.0370

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.000683

Gnomad FIN exome AF: 0.0557

Gnomad NFE exome AF: 0.0473

Gnomad OTH exome AF: 0.0422

GnomAD4 exome AF: 0.0409 AC: 58056 AN: 1419130 Hom.: 1330 Cov.: 26 AF XY: 0.0405 AC XY: 28647 AN XY: 707868

African (AFR) AF: 0.0299 AC: 977 AN: 32656

American (AMR) AF: 0.0205 AC: 898 AN: 43714

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 603 AN: 25788

East Asian (EAS) AF: 0.000204 AC: 8 AN: 39294

South Asian (SAS) AF: 0.0302 AC: 2556 AN: 84660

European-Finnish (FIN) AF: 0.0540 AC: 2863 AN: 53010

Middle Eastern (MID) AF: 0.0689 AC: 392 AN: 5688

European-Non Finnish (NFE) AF: 0.0441 AC: 47440 AN: 1075362

Other (OTH) AF: 0.0393 AC: 2319 AN: 58958

GnomAD4 genome AF: 0.0374 AC: 5698 AN: 152308 Hom.: 120 Cov.: 32 AF XY: 0.0374 AC XY: 2782 AN XY: 74482

African (AFR) AF: 0.0333 AC: 1384 AN: 41564

American (AMR) AF: 0.0201 AC: 308 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 73 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4834

European-Finnish (FIN) AF: 0.0559 AC: 594 AN: 10624

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3099 AN: 68022

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0407 Hom.: 40

Bravo AF: 0.0333

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Malignant hyperthermia, susceptibility to, 5 (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	not specified (2)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	not provided (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.0
DANN	Benign	0.67
PhyloP100		0.85
Mutation Taster		=100/0	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: rs113792034; hg19: chr1-201035087;