1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001232.4(CASQ2):c.738-11_738-5del variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00124 in 1,401,858 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 0)
  • Exomes 𝑓: 0.00091 (2 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.12

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-115725557-GAAAAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAAAAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 502421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAAAAAA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00506 (577/114004) while in subpopulation AFR AF= 0.0163 (503/30844). AF 95% confidence interval is 0.0151. There are 6 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.738-11_738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6	c.738-11_738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.*110-11_*110-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 574 AN: 114034 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00233

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00105

Gnomad SAS AF: 0.00639

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000317

Gnomad OTH AF: 0.00453

GnomAD4 exome AF: 0.000907 AC: 1168 AN: 1287854 Hom.: 2 AF XY: 0.000988 AC XY: 634 AN XY: 641506

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.000849

Gnomad4 ASJ exome AF: 0.000176

Gnomad4 EAS exome AF: 0.000713

Gnomad4 SAS exome AF: 0.00518

Gnomad4 FIN exome AF: 0.000162

Gnomad4 NFE exome AF: 0.000257

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00506 AC: 577 AN: 114004 Hom.: 6 Cov.: 0 AF XY: 0.00558 AC XY: 295 AN XY: 52884

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00233

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00105

Gnomad4 SAS AF: 0.00644

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000317

Gnomad4 OTH AF: 0.00452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 06, 2017

- -

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 24, 2021

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178;