3-10372031-G-A

Position:

• chr3-10372031-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001001331.4(ATP2B2):​c.1437C>T​(p.Asn479=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,613,946 control chromosomes in the GnomAD database, including 75,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6052 hom., cov: 32)
  • Exomes 𝑓: 0.31 (68980 hom.)
• Consequence: ATP2B2 NM_001001331.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 1.74

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 3-10372031-G-A is Benign according to our data. Variant chr3-10372031-G-A is described in ClinVar as [Benign]. Clinvar id is 1291136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2B2	NM_001001331.4	c.1437C>T	p.Asn479=	synonymous_variant	12/23	ENST00000360273.7	NP_001001331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2B2	ENST00000360273.7	c.1437C>T	p.Asn479=	synonymous_variant	12/23	5	NM_001001331.4	ENSP00000353414

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41328 AN: 152010 Hom.: 6059 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.308 AC: 77453 AN: 251400 Hom.: 12305 AF XY: 0.312 AC XY: 42435 AN XY: 135872

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.343

Gnomad ASJ exome AF: 0.312

Gnomad EAS exome AF: 0.318

Gnomad SAS exome AF: 0.360

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.305

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.306 AC: 447228 AN: 1461818 Hom.: 68980 Cov.: 49 AF XY: 0.308 AC XY: 223847 AN XY: 727212

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.316

Gnomad4 EAS exome AF: 0.299

Gnomad4 SAS exome AF: 0.356

Gnomad4 FIN exome AF: 0.294

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.272 AC: 41342 AN: 152128 Hom.: 6052 Cov.: 32 AF XY: 0.274 AC XY: 20392 AN XY: 74382

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.346

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.277

Alfa AF: 0.296 Hom.: 8436

Bravo AF: 0.267

Asia WGS AF: 0.295 AC: 1028 AN: 3478

EpiCase AF: 0.303

EpiControl AF: 0.305

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Associated with severe COVID-19 disease Pathogenic:1

Likely risk allele, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Jul 01, 2023

The allele G is a risk for non-surviving in patients with severe COVID-19 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.3
DANN	Benign	0.70

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: rs2289274; hg19: chr3-10413715; COSMIC: COSV59492170;