rs781062859

Positions:

• chr1-115744836-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001232.4(CASQ2):​c.311A>C​(p.Lys104Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CASQ2 NM_001232.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.311A>C	p.Lys104Thr	missense_variant	2/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6	c.311A>C	p.Lys104Thr	missense_variant	2/11	1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.35A>C	p.Lys12Thr	missense_variant, NMD_transcript_variant	3/13	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251214 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460308 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 06, 2016

The p.Lys104Thr variant in CASQ2 has not been previously reported in individuals with cardiomyopathy, but was identified in 1/11251 Latino chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs781062 859). Computational prediction tools and conservation analysis suggest that the p.Lys104Thr variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. In summary, the clinical significance o f the p.Lys104Thr variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.46
MutPred		0.84		Gain of ubiquitination at K105 (P = 0.034);
MVP		0.95
MPC		0.25
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs781062859; hg19: chr1-116287457;