1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAA

Position:

• chr1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The ENST00000261448.6(CASQ2):​c.738-10_738-5del variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00124 in 1,399,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: CASQ2 ENST00000261448.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-115725557-GAAAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAAAA-G is described in ClinVar as [Benign]. Clinvar id is 917550.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAAA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000623 (71/114000) while in subpopulation NFE AF= 0.000952 (54/56720). AF 95% confidence interval is 0.000749. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.738-10_738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.738-10_738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001232.4	ENSP00000261448	P1
CASQ2	ENST00000488931.2	c.*110-10_*110-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3		ENSP00000518226

Frequencies

GnomAD3 genomes AF: 0.000623 AC: 71 AN: 114030 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000388

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000952

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00130 AC: 1671 AN: 1285780 Hom.: 0 AF XY: 0.00124 AC XY: 795 AN XY: 640494

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.000440

Gnomad4 EAS exome AF: 0.000770

Gnomad4 SAS exome AF: 0.000372

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000623 AC: 71 AN: 114000 Hom.: 0 Cov.: 0 AF XY: 0.000586 AC XY: 31 AN XY: 52882

Gnomad4 AFR AF: 0.000389

Gnomad4 AMR AF: 0.000388

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000952

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 06, 2020

Variant summary: CASQ2 c.738-10_738-5delTTTTTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 179292 control chromosomes. However, the variant is located in a homopolymer region of 20 Ts, which is a highly polymorphic region. Therefore, suggesting the region is tolerable to changes in length of poly Ts. To our knowledge, no occurrence of c.738-10_738-5delTTTTTT in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

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;