NM_001232.4:c.226G>A

Variant names:

• chr1-115768316-C-T
• rs10801999
• NM_001232.4:c.226G>A

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.226G>A​(p.Val76Met) variant causes a missense change. The variant allele was found at a frequency of 0.00964 in 1,610,530 control chromosomes in the GnomAD database, including 824 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. V76T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (88 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (736 hom.)
• Consequence: CASQ2 NM_001232.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 5.86
• Publications: 22 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: AD, AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, 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=0.002249509).
• BP6: Variant 1-115768316-C-T is Benign according to our data. Variant chr1-115768316-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0757 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.226G>A	p.Val76Met	missense	Exon 1 of 11	NP_001223.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	ENST00000261448.6	TSL:1 MANE Select	c.226G>A	p.Val76Met	missense	Exon 1 of 11	ENSP00000261448.5
	CASQ2	ENST00000713728.1		c.-51G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	ENSP00000519032.1
	CASQ2	ENST00000850611.1		c.-459G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	ENSP00000520899.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2192 AN: 152144 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0792

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0713

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.0317 AC: 7968 AN: 251022 AF XY: 0.0262

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0658

Gnomad FIN exome AF: 0.0261

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.0237

GnomAD4 exome AF: 0.00914 AC: 13332 AN: 1458268 Hom.: 736 Cov.: 30 AF XY: 0.00870 AC XY: 6313 AN XY: 725764

African (AFR) AF: 0.00168 AC: 56 AN: 33386

American (AMR) AF: 0.149 AC: 6644 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26110

East Asian (EAS) AF: 0.0752 AC: 2981 AN: 39660

South Asian (SAS) AF: 0.0131 AC: 1132 AN: 86170

European-Finnish (FIN) AF: 0.0254 AC: 1356 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5760

European-Non Finnish (NFE) AF: 0.000532 AC: 590 AN: 1108782

Other (OTH) AF: 0.00924 AC: 557 AN: 60266

GnomAD4 genome AF: 0.0144 AC: 2196 AN: 152262 Hom.: 88 Cov.: 32 AF XY: 0.0174 AC XY: 1292 AN XY: 74448

African (AFR) AF: 0.00298 AC: 124 AN: 41556

American (AMR) AF: 0.0794 AC: 1214 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0714 AC: 369 AN: 5166

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4830

European-Finnish (FIN) AF: 0.0272 AC: 288 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68030

Other (OTH) AF: 0.0161 AC: 34 AN: 2108

Alfa AF: 0.00773 Hom.: 211

Bravo AF: 0.0199

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0251 AC: 3042

Asia WGS AF: 0.0310 AC: 108 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Catecholaminergic polymorphic ventricular tachycardia 2 (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0022	T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.25
Sift	Benign	0.45	T
Sift4G	Benign	0.32	T
Polyphen		0.82	P
Vest4		0.23
MPC		0.32
ClinPred		0.021	T
GERP RS		5.5
PromoterAI		-0.072	Neutral
Varity_R		0.29
gMVP		0.64
Mutation Taster		=68/32	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: rs10801999; hg19: chr1-116310937; COSMIC: COSV54768445;