3-10359892-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001001331.4(ATP2B2):c.1891G>A(p.Val631Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00943 in 1,614,226 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (126 hom.)
• Consequence: ATP2B2 NM_001001331.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 2.19

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.

• PP2: Missense variant where missense usually causes diseases, ATP2B2
• BP4: Computational evidence support a benign effect (MetaRNN=0.00996235).
• BP6: Variant 3-10359892-C-T is Benign according to our data. Variant chr3-10359892-C-T is described in ClinVar as [Benign]. Clinvar id is 17801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00788 (1200/152356) while in subpopulation AMR AF= 0.028 (428/15306). AF 95% confidence interval is 0.0258. There are 17 homozygotes in gnomad4. There are 604 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B2	NM_001001331.4	c.1891G>A	p.Val631Met	missense_variant	13/23	ENST00000360273.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B2	ENST00000360273.7	c.1891G>A	p.Val631Met	missense_variant	13/23	5	NM_001001331.4

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1193 AN: 152238 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00289

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00883

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.0115 AC: 2877 AN: 250766 Hom.: 54 AF XY: 0.0104 AC XY: 1405 AN XY: 135618

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.0477

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00840

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00960 AC: 14027 AN: 1461870 Hom.: 126 Cov.: 31 AF XY: 0.00926 AC XY: 6731 AN XY: 727238

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.0457

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00391

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00989

Gnomad4 OTH exome AF: 0.00813

GnomAD4 genome AF: 0.00788 AC: 1200 AN: 152356 Hom.: 17 Cov.: 33 AF XY: 0.00811 AC XY: 604 AN XY: 74500

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.0280

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00882

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00793 Hom.: 7

Bravo AF: 0.00967

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00881 AC: 1069

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00717

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ATP2B2: BP1, BS1, BS2 -

Agenesis of the corpus callosum with peripheral neuropathy Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Val586Met variant, sometimes called p.Val631Met due to a difference in cDNA numbering, in ATP2B2 has been identified in at least 5 individuals with hearing loss, including 3 siblings from 1 family (PMID: 15829536). Of note, 2 additional siblings in the same family did not have this variant and are less severely affected by disease. All 5 siblings were reported to be homozygous for a separate, causal variant in CDH23 (PMID: 15829536). This variant has also been identified in >4% of Latino chromosomes and 22 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Val586Met variant may have a mild impact on protein function (PMID: 22047666). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive deafness but may modify disease. -

ATP2B2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Deafness, autosomal recessive 12, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 14, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.86	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.24	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.16	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.85	.;P;.;.;.;.;.;.;P;.;.
Vest4		0.40
MPC		1.8
ClinPred		0.012	T
GERP RS		4.9
Varity_R		0.17
gMVP		0.83

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: rs61736451; hg19: chr3-10401576;