1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAA

Variant names:

• chr1-115725557-GAAAAAA-G
• rs56889721
• NM_001232.4:c.738-10_738-5delTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001232.4(CASQ2):​c.738-10_738-5delTTTTTT variant causes a splice region, 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 NM_001232.4 splice_region, 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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 0. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.738-10_738-5delTTTTTT		splice_region_variant, intron_variant	Intron 6 of 10	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.738-10_738-5delTTTTTT		splice_region_variant, intron_variant	Intron 6 of 10	1	NM_001232.4	ENSP00000261448.5
CASQ2	ENST00000488931.2	n.*110-10_*110-5delTTTTTT		splice_region_variant, intron_variant	Intron 8 of 12	3		ENSP00000518226.1

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 AC: 44 AN: 28282

Gnomad4 AMR exome AF: 0.00132 AC: 42 AN: 31746

Gnomad4 ASJ exome AF: 0.000440 AC: 10 AN: 22710

Gnomad4 EAS exome AF: 0.000770 AC: 28 AN: 36358

Gnomad4 SAS exome AF: 0.000372 AC: 27 AN: 72610

Gnomad4 FIN exome AF: 0.00167 AC: 62 AN: 37060

Gnomad4 NFE exome AF: 0.00138 AC: 1384 AN: 999998

Gnomad4 Remaining exome AF: 0.00133 AC: 71 AN: 53348

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 AC: 0.00038908 AN: 0.00038908

Gnomad4 AMR AF: 0.000388 AC: 0.000388123 AN: 0.000388123

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000283 AC: 0.000283447 AN: 0.000283447

Gnomad4 NFE AF: 0.000952 AC: 0.000952045 AN: 0.000952045

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000917 Hom.: 284

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 06, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=68/32	polymorphism

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;