rs28730712

Variant names:

• chr1-115702930-A-G
• rs28730712
• NM_001232.4:c.1005T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-115702930-A-G
• chr1-115702930-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001232.4(CASQ2):​c.1005T>C​(p.Asn335Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,613,282 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (88 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (101 hom.)
• Consequence: CASQ2 NM_001232.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.605
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-115702930-A-G is Benign according to our data. Variant chr1-115702930-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.605 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.064 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.1005T>C	p.Asn335Asn	synonymous	Exon 10 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.1005T>C	p.Asn335Asn	synonymous	Exon 10 of 11	ENSP00000261448.5	O14958-1
	CASQ2	ENST00000713711.1		c.1146T>C	p.Asn382Asn	synonymous	Exon 11 of 12	ENSP00000519014.1	A0AAQ5BGS1
	CASQ2	ENST00000874188.1		c.828T>C	p.Asn276Asn	synonymous	Exon 8 of 9	ENSP00000544247.1

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2964 AN: 152166 Hom.: 87 Cov.: 33

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.00531 AC: 1329 AN: 250068 AF XY: 0.00408

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.00489

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000636

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00234 AC: 3412 AN: 1460998 Hom.: 101 Cov.: 30 AF XY: 0.00208 AC XY: 1512 AN XY: 726758

African (AFR) AF: 0.0689 AC: 2302 AN: 33422

American (AMR) AF: 0.00452 AC: 202 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00544 AC: 142 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5760

European-Non Finnish (NFE) AF: 0.000316 AC: 351 AN: 1111570

Other (OTH) AF: 0.00543 AC: 328 AN: 60354

GnomAD4 genome AF: 0.0195 AC: 2975 AN: 152284 Hom.: 88 Cov.: 33 AF XY: 0.0185 AC XY: 1380 AN XY: 74470

African (AFR) AF: 0.0661 AC: 2746 AN: 41558

American (AMR) AF: 0.00850 AC: 130 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68016

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.00910 Hom.: 32

Bravo AF: 0.0223

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Catecholaminergic polymorphic ventricular tachycardia 2 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	Caudal regression sequence (1)
-	-	1	Neural tube defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.6
DANN	Benign	0.79
PhyloP100		0.60
Mutation Taster		=91/9	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: rs28730712; hg19: chr1-116245551;