rs4074536

Variant names:

• chr1-115768346-T-C
• rs4074536
• NM_001232.4:c.196A>G
• CASQ2 p.Thr66Ala

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.196A>G​(p.Thr66Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,612,466 control chromosomes in the GnomAD database, including 79,340 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T66V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.35 (9637 hom., cov: 31)
  • Exomes 𝑓: 0.30 (69703 hom.)
• Consequence: CASQ2 NM_001232.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.63
• Publications: 67 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 (MetaRNN=7.7494435E-5).
• BP6: Variant 1-115768346-T-C is Benign according to our data. Variant chr1-115768346-T-C is described in ClinVar as Benign. ClinVar VariationId is 44160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.512 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.196A>G	p.Thr66Ala	missense	Exon 1 of 11	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.196A>G	p.Thr66Ala	missense	Exon 1 of 11	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.196A>G	p.Thr66Ala	missense	Exon 1 of 12	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.196A>G	p.Thr66Ala	missense	Exon 1 of 10	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52384 AN: 151828 Hom.: 9617 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.343

GnomAD2 exomes AF: 0.329 AC: 82656 AN: 251288 AF XY: 0.324

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.549

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.304 AC: 443580 AN: 1460520 Hom.: 69703 Cov.: 34 AF XY: 0.303 AC XY: 219822 AN XY: 726622

African (AFR) AF: 0.454 AC: 15169 AN: 33440

American (AMR) AF: 0.359 AC: 16056 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 6757 AN: 26130

East Asian (EAS) AF: 0.520 AC: 20641 AN: 39690

South Asian (SAS) AF: 0.304 AC: 26194 AN: 86218

European-Finnish (FIN) AF: 0.275 AC: 14675 AN: 53420

Middle Eastern (MID) AF: 0.409 AC: 2357 AN: 5766

European-Non Finnish (NFE) AF: 0.290 AC: 322687 AN: 1110804

Other (OTH) AF: 0.316 AC: 19044 AN: 60336

GnomAD4 genome AF: 0.345 AC: 52445 AN: 151946 Hom.: 9637 Cov.: 31 AF XY: 0.347 AC XY: 25742 AN XY: 74276

African (AFR) AF: 0.448 AC: 18562 AN: 41406

American (AMR) AF: 0.347 AC: 5306 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 874 AN: 3470

East Asian (EAS) AF: 0.528 AC: 2713 AN: 5134

South Asian (SAS) AF: 0.312 AC: 1504 AN: 4816

European-Finnish (FIN) AF: 0.286 AC: 3018 AN: 10566

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19206 AN: 67958

Other (OTH) AF: 0.346 AC: 731 AN: 2114

Alfa AF: 0.312 Hom.: 38150

Bravo AF: 0.361

Asia WGS AF: 0.382 AC: 1330 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.303

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Catecholaminergic polymorphic ventricular tachycardia 2 (5)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.7
DANN	Benign	0.18
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.0078	T
MetaRNN	Benign	0.000077	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.086
Sift	Benign	0.94	T
Sift4G	Benign	1.0	T
PromoterAI		0.023	Neutral
Varity_R		0.083
gMVP		0.20
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4074536;

hg19: chr1-116310967;

COSMIC: COSV54768455;