1-203683224-C-A

Variant summary

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

The NM_001684.5(ATP2B4):c.19C>A(p.Arg7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,613,910 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (51 hom.)
• Consequence: ATP2B4 NM_001684.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.93

Genes affected

ATP2B4 (HGNC:817): (ATPase plasma membrane Ca2+ transporting 4) 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 4. 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, ATP2B4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025470853).
• BP6: Variant 1-203683224-C-A is Benign according to our data. Variant chr1-203683224-C-A is described in ClinVar as [Benign]. Clinvar id is 705092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00423 (644/152262) while in subpopulation EAS AF= 0.0222 (115/5190). AF 95% confidence interval is 0.0189. There are 14 homozygotes in gnomad4. There are 464 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 642 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B4	NM_001684.5	c.19C>A	p.Arg7Ser	missense_variant	2/21	ENST00000357681.10
ATP2B4	NM_001001396.3	c.19C>A	p.Arg7Ser	missense_variant	2/22
ATP2B4	NM_001365783.2	c.19C>A	p.Arg7Ser	missense_variant	2/21
ATP2B4	NM_001365784.2	c.19C>A	p.Arg7Ser	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B4	ENST00000357681.10	c.19C>A	p.Arg7Ser	missense_variant	2/21	1	NM_001684.5	A1
ATP2B4	ENST00000341360.7	c.19C>A	p.Arg7Ser	missense_variant	2/22	1		P4
ATP2B4	ENST00000705901.1	c.19C>A	p.Arg7Ser	missense_variant	2/21

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 642 AN: 152144 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0429

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00561 AC: 1409 AN: 251060 Hom.: 29 AF XY: 0.00518 AC XY: 703 AN XY: 135670

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0222

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.0377

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00211 AC: 3083 AN: 1461648 Hom.: 51 Cov.: 29 AF XY: 0.00196 AC XY: 1426 AN XY: 727134

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0183

Gnomad4 SAS exome AF: 0.000824

Gnomad4 FIN exome AF: 0.0330

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.00423 AC: 644 AN: 152262 Hom.: 14 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74432

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0222

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0429

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00124 Hom.: 3

Bravo AF: 0.00128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00486 AC: 590

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ATP2B4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.84	T;T;.
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.26	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.017	B;.;.
Vest4		0.12
MVP		0.32
MPC		0.54
ClinPred		0.023	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.35

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: rs146234576; hg19: chr1-203652352; COSMIC: COSV58180450;