rs28730716

Variant names:

• chr1-115726998-T-C
• rs28730716
• NM_001232.4:c.731A>G

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.731A>G​(p.His244Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,572,306 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H244C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (135 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (109 hom.)
• Consequence: CASQ2 NM_001232.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:20
• Conservation: PhyloP100: 7.53
• Publications: 9 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 (MetaRNN=0.006117046).
• BP6: Variant 1-115726998-T-C is Benign according to our data. Variant chr1-115726998-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.078 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.731A>G	p.His244Arg	missense	Exon 6 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.731A>G	p.His244Arg	missense	Exon 6 of 11	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.872A>G	p.His291Arg	missense	Exon 7 of 12	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874189.1		c.731A>G	p.His244Arg	missense	Exon 6 of 10	ENSP00000544248.1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3503 AN: 149876 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000434

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.0184

GnomAD2 exomes AF: 0.00623 AC: 1559 AN: 250200 AF XY: 0.00443

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.00429

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00234 AC: 3333 AN: 1422298 Hom.: 109 Cov.: 33 AF XY: 0.00197 AC XY: 1393 AN XY: 707530

African (AFR) AF: 0.0818 AC: 2664 AN: 32556

American (AMR) AF: 0.00495 AC: 216 AN: 43634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24810

East Asian (EAS) AF: 0.00 AC: 0 AN: 36866

South Asian (SAS) AF: 0.000175 AC: 15 AN: 85636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48990

Middle Eastern (MID) AF: 0.00364 AC: 20 AN: 5496

European-Non Finnish (NFE) AF: 0.000118 AC: 128 AN: 1086388

Other (OTH) AF: 0.00501 AC: 290 AN: 57922

GnomAD4 genome AF: 0.0234 AC: 3508 AN: 150008 Hom.: 135 Cov.: 32 AF XY: 0.0225 AC XY: 1647 AN XY: 73294

African (AFR) AF: 0.0802 AC: 3300 AN: 41128

American (AMR) AF: 0.0104 AC: 158 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4966

South Asian (SAS) AF: 0.000434 AC: 2 AN: 4610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67376

Other (OTH) AF: 0.0183 AC: 38 AN: 2082

Alfa AF: 0.00753 Hom.: 149

Bravo AF: 0.0268

ESP6500AA AF: 0.0783 AC: 345

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00767 AC: 931

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	7	not specified (8)
-	-	5	Catecholaminergic polymorphic ventricular tachycardia 2 (5)
-	-	3	not provided (3)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0061	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.89	P
Vest4		0.79
MVP		0.99
MPC		0.17
ClinPred		0.026	T
GERP RS		5.8
Varity_R		0.81
gMVP		0.92
Mutation Taster		=62/38	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: rs28730716; hg19: chr1-116269619;