1-115726999-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_001232.4(CASQ2):c.730C>T(p.His244Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,608,828 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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 0.00073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 1 hom. )

Consequence

CASQ2
NM_001232.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.28

Publications

6 publications found

Variant links:

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

CASQ2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07780275).

BP6

Variant 1-115726999-G-A is Benign according to our data. Variant chr1-115726999-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227210.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00073 (111/151972) while in subpopulation AFR AF = 0.00241 (100/41444). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.730C>T	p.His244Tyr	missense	Exon 6 of 11	NP_001223.2	O14958-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASQ2	ENST00000261448.6	TSL:1 MANE Select	c.730C>T	p.His244Tyr	missense	Exon 6 of 11	ENSP00000261448.5	O14958-1
CASQ2	ENST00000713711.1		c.871C>T	p.His291Tyr	missense	Exon 7 of 12	ENSP00000519014.1	A0AAQ5BGS1
CASQ2	ENST00000874189.1		c.730C>T	p.His244Tyr	missense	Exon 6 of 10	ENSP00000544248.1

Frequencies

GnomAD3 genomes

AF:

0.000731

AC:

111

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000188

AC:

AN:

250308

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000680

AC:

AN:

1456856

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

724742

show subpopulations

African (AFR)

AF:

0.00204

AC:

AN:

33374

American (AMR)

AF:

0.000224

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39480

South Asian (SAS)

AF:

0.00

AC:

AN:

86054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108714

Other (OTH)

AF:

0.000350

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000730

AC:

111

AN:

151972

Hom.:

Cov.:

AF XY:

0.000794

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.00241

AC:

100

AN:

41444

American (AMR)

AF:

0.000524

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67970

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000310

Hom.:

Bravo

AF:

0.000733

ExAC

AF:

0.000214

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia 2 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.068

MetaRNN

Benign

0.078

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.5

PhyloP100

5.3

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.76

MVP

0.98

MPC

0.29

ClinPred

0.081

GERP RS

5.8

Varity_R

0.75

gMVP

0.90

Mutation Taster

=45/55

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over