rs146664754

Variant names:

• chr1-115732940-G-C
• rs146664754
• NM_001232.4:c.567C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-115732940-G-C
• chr1-115732940-G-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001232.4(CASQ2):​c.567C>G​(p.Phe189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000752 in 1,613,870 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (3 hom.)
• Consequence: CASQ2 NM_001232.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:9
• Conservation: PhyloP100: 1.71
• Publications: 16 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05320248).
• BP6: Variant 1-115732940-G-C is Benign according to our data. Variant chr1-115732940-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162814.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000532 (81/152284) while in subpopulation AMR AF = 0.000719 (11/15302). AF 95% confidence interval is 0.000495. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.567C>G	p.Phe189Leu	missense	Exon 5 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.567C>G	p.Phe189Leu	missense	Exon 5 of 11	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000850611.1		c.-64C>G		5_prime_UTR_premature_start_codon_gain	Exon 7 of 13	ENSP00000520899.1	A0ABB0MVM1
	CASQ2	ENST00000713711.1		c.708C>G	p.Phe236Leu	missense	Exon 6 of 12	ENSP00000519014.1	A0AAQ5BGS1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000716 AC: 180 AN: 251354 AF XY: 0.000721

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000775 AC: 1132 AN: 1461586 Hom.: 3 Cov.: 30 AF XY: 0.000763 AC XY: 555 AN XY: 727120

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00842 AC: 220 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86246

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.000699 AC: 777 AN: 1111798

Other (OTH) AF: 0.00118 AC: 71 AN: 60376

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74452

African (AFR) AF: 0.0000481 AC: 2 AN: 41542

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	4	-	Catecholaminergic polymorphic ventricular tachycardia 2 (4)
-	1	1	Cardiomyopathy (2)
-	1	1	Cardiovascular phenotype (2)
-	1	1	not specified (2)
-	-	1	CASQ2-related disorder (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	1	-	Polymorphic ventricular tachycardia (1)
-	-	1	Sudden unexplained death (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.053	T
MetaSVM	Uncertain	0.052	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.022	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.97		Loss of sheet (P = 0.0817)
MVP		0.92
MPC		0.34
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.87
gMVP		0.75
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs146664754; hg19: chr1-116275561; COSMIC: COSV54769793; COSMIC: COSV54769793;