3-10338239-C-T

Position:

• chr3-10338239-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001001331.4(ATP2B2):​c.3357G>A​(p.Ala1119=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,613,952 control chromosomes in the GnomAD database, including 166,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17883 hom., cov: 33)
  • Exomes 𝑓: 0.44 (148137 hom.)
• Consequence: ATP2B2 NM_001001331.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.53

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3600707E-5).
• BP6: Variant 3-10338239-C-T is Benign according to our data. Variant chr3-10338239-C-T is described in ClinVar as [Benign]. Clinvar id is 1273978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2B2	NM_001001331.4	c.3357G>A	p.Ala1119=	synonymous_variant	22/23	ENST00000360273.7	NP_001001331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2B2	ENST00000360273.7	c.3357G>A	p.Ala1119=	synonymous_variant	22/23	5	NM_001001331.4	ENSP00000353414

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72478 AN: 151986 Hom.: 17869 Cov.: 33

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.491 AC: 123399 AN: 251364 Hom.: 32223 AF XY: 0.488 AC XY: 66252 AN XY: 135864

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.689

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.547

Gnomad SAS exome AF: 0.620

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.443 AC: 648055 AN: 1461850 Hom.: 148137 Cov.: 69 AF XY: 0.447 AC XY: 325286 AN XY: 727226

Gnomad4 AFR exome AF: 0.552

Gnomad4 AMR exome AF: 0.677

Gnomad4 ASJ exome AF: 0.384

Gnomad4 EAS exome AF: 0.594

Gnomad4 SAS exome AF: 0.619

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.445

GnomAD4 genome AF: 0.477 AC: 72536 AN: 152102 Hom.: 17883 Cov.: 33 AF XY: 0.482 AC XY: 35852 AN XY: 74340

Gnomad4 AFR AF: 0.547

Gnomad4 AMR AF: 0.581

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.619

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.413

Gnomad4 OTH AF: 0.460

Alfa AF: 0.432 Hom.: 6770

Bravo AF: 0.493

TwinsUK AF: 0.415 AC: 1538

ALSPAC AF: 0.424 AC: 1635

ESP6500AA AF: 0.537 AC: 2365

ESP6500EA AF: 0.415 AC: 3570

ExAC AF: 0.486 AC: 59068

Asia WGS AF: 0.578 AC: 2012 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.408

ClinVar

Significance: Benign

Submissions summary: 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	Jun 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.035
DANN	Benign	0.94
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.000034	T
MutationTaster	Benign	6.1e-14	P;P;P;P;P
GERP RS		-9.2

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: rs35678; hg19: chr3-10379923; COSMIC: COSV59497074;