rs9333652

Variant names:

• chr1-201073490-G-A
• rs9333652
• NM_000069.3:c.2157+59C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201073490-G-A
• chr1-201073490-G-C
• chr1-201073490-G-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.2157+59C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,360,698 control chromosomes in the GnomAD database, including 152,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16107 hom., cov: 32)
  • Exomes 𝑓: 0.45 (136634 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.120
• Publications: 7 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=-0.85).
• BP6: Variant 1-201073490-G-A is Benign according to our data. Variant chr1-201073490-G-A is described in ClinVar as Benign. ClinVar VariationId is 678298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.937 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.2157+59C>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.2157+59C>T		intron	N/A	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.2157+59C>T		intron	N/A	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.2157+59C>T		intron	N/A	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66732 AN: 151800 Hom.: 16095 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.959

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.441

GnomAD4 exome AF: 0.453 AC: 547790 AN: 1208780 Hom.: 136634 AF XY: 0.463 AC XY: 284491 AN XY: 614078

African (AFR) AF: 0.347 AC: 9899 AN: 28528

American (AMR) AF: 0.564 AC: 25035 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 11594 AN: 24602

East Asian (EAS) AF: 0.964 AC: 37187 AN: 38570

South Asian (SAS) AF: 0.740 AC: 60185 AN: 81368

European-Finnish (FIN) AF: 0.566 AC: 29824 AN: 52686

Middle Eastern (MID) AF: 0.528 AC: 2764 AN: 5230

European-Non Finnish (NFE) AF: 0.393 AC: 346508 AN: 881154

Other (OTH) AF: 0.475 AC: 24794 AN: 52242

GnomAD4 genome AF: 0.440 AC: 66769 AN: 151918 Hom.: 16107 Cov.: 32 AF XY: 0.457 AC XY: 33893 AN XY: 74244

African (AFR) AF: 0.345 AC: 14287 AN: 41414

American (AMR) AF: 0.477 AC: 7283 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1633 AN: 3468

East Asian (EAS) AF: 0.959 AC: 4956 AN: 5168

South Asian (SAS) AF: 0.763 AC: 3676 AN: 4820

European-Finnish (FIN) AF: 0.581 AC: 6118 AN: 10532

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.402 AC: 27282 AN: 67928

Other (OTH) AF: 0.447 AC: 943 AN: 2110

Alfa AF: 0.389 Hom.: 2749

Bravo AF: 0.429

Asia WGS AF: 0.819 AC: 2842 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	-0.85
CADD	Benign	1.4
DANN	Benign	0.28
PhyloP100		0.12
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: rs9333652; hg19: chr1-201042618;