rs3811003

Variant names:

• chr1-115705169-G-A
• rs3811003
• NM_001232.4:c.939+23C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-115705169-G-A
• chr1-115705169-G-C

Variant summary

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

The NM_001232.4(CASQ2):​c.939+23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,440,028 control chromosomes in the GnomAD database, including 83,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12731 hom., cov: 33)
  • Exomes 𝑓: 0.33 (71065 hom.)
• Consequence: CASQ2 NM_001232.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.198
• Publications: 7 publications found

Genes affected

CASQ2 (HGNC:1513): (calsequestrin 2) The protein encoded by this gene specifies the cardiac muscle family member of the calsequestrin family. Calsequestrin is localized to the sarcoplasmic reticulum in cardiac and slow skeletal muscle cells. The protein is a calcium binding protein that stores calcium for muscle function. Mutations in this gene cause stress-induced polymorphic ventricular tachycardia, also referred to as catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2), a disease characterized by bidirectional ventricular tachycardia that may lead to cardiac arrest. [provided by RefSeq, Jul 2008]

CASQ2 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-115705169-G-A is Benign according to our data. Variant chr1-115705169-G-A is described in ClinVar as Benign. ClinVar VariationId is 257653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001232.4. 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
	CASQ2	NM_001232.4	MANE Select	c.939+23C>T		intron	N/A	NP_001223.2	O14958-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	ENST00000261448.6	TSL:1 MANE Select	c.939+23C>T		intron	N/A	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.1080+23C>T		intron	N/A	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.939+23C>T		intron	N/A	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59140 AN: 152026 Hom.: 12719 Cov.: 33

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.346 AC: 86909 AN: 251060 AF XY: 0.338

Gnomad AFR exome AF: 0.569

Gnomad AMR exome AF: 0.366

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.520

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.327

GnomAD4 exome AF: 0.326 AC: 419445 AN: 1287882 Hom.: 71065 Cov.: 19 AF XY: 0.323 AC XY: 210046 AN XY: 650278

African (AFR) AF: 0.565 AC: 16994 AN: 30080

American (AMR) AF: 0.364 AC: 16196 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 6914 AN: 25072

East Asian (EAS) AF: 0.479 AC: 18614 AN: 38868

South Asian (SAS) AF: 0.293 AC: 24276 AN: 82944

European-Finnish (FIN) AF: 0.295 AC: 15740 AN: 53360

Middle Eastern (MID) AF: 0.369 AC: 1965 AN: 5330

European-Non Finnish (NFE) AF: 0.315 AC: 300031 AN: 953072

Other (OTH) AF: 0.343 AC: 18715 AN: 54640

GnomAD4 genome AF: 0.389 AC: 59194 AN: 152146 Hom.: 12731 Cov.: 33 AF XY: 0.388 AC XY: 28861 AN XY: 74380

African (AFR) AF: 0.564 AC: 23386 AN: 41488

American (AMR) AF: 0.336 AC: 5137 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1006 AN: 3468

East Asian (EAS) AF: 0.510 AC: 2629 AN: 5158

South Asian (SAS) AF: 0.292 AC: 1408 AN: 4828

European-Finnish (FIN) AF: 0.316 AC: 3346 AN: 10592

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 21024 AN: 68004

Other (OTH) AF: 0.370 AC: 782 AN: 2114

Alfa AF: 0.337 Hom.: 25112

Bravo AF: 0.401

Asia WGS AF: 0.381 AC: 1328 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.0
DANN	Benign	0.77
PhyloP100		-0.20
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: rs3811003; hg19: chr1-116247790; COSMIC: COSV54768530;