chr3-10329025-C-T

Variant names:

• chr3-10329025-C-T
• rs1215036750
• NM_001001331.4:c.3521G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001001331.4(ATP2B2):​c.3521G>A​(p.Arg1174Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATP2B2 NM_001001331.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

Genes affected

ATP2B2 (HGNC:815): (ATPase plasma membrane Ca2+ transporting 2) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B2	NM_001001331.4	c.3521G>A	p.Arg1174Gln	missense_variant	Exon 23 of 23	ENST00000360273.7	NP_001001331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2B2	ENST00000360273.7	c.3521G>A	p.Arg1174Gln	missense_variant	Exon 23 of 23	5	NM_001001331.4	ENSP00000353414.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151858 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151858 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74138

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1129 of the ATP2B2 protein (p.Arg1129Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP2B2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP2B2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;.;.;.;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D;D;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.6	.;L;.;.;.;.;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;N;N;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.22	T;T;T;.;.;.;.
Sift4G	Benign	0.61	T;T;T;.;.;.;.
Polyphen		0.31	.;B;.;.;.;.;B
Vest4		0.41
MutPred		0.22		.;Gain of sheet (P = 0.0827);.;.;.;.;Gain of sheet (P = 0.0827);
MVP		0.56
MPC		1.9
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1215036750; hg19: chr3-10370709; COSMIC: COSV59497773; COSMIC: COSV59497773;