1-203683210-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001684.5(ATP2B4):c.5C>T(p.Thr2Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,613,070 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (5 hom.)
• Consequence: ATP2B4 NM_001684.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.17

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATP2B4
• BP4: Computational evidence support a benign effect (MetaRNN=0.010277808).
• BP6: Variant 1-203683210-C-T is Benign according to our data. Variant chr1-203683210-C-T is described in ClinVar as [Benign]. Clinvar id is 1626186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B4	NM_001684.5	c.5C>T	p.Thr2Met	missense_variant	2/21	ENST00000357681.10
ATP2B4	NM_001001396.3	c.5C>T	p.Thr2Met	missense_variant	2/22
ATP2B4	NM_001365783.2	c.5C>T	p.Thr2Met	missense_variant	2/21
ATP2B4	NM_001365784.2	c.5C>T	p.Thr2Met	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B4	ENST00000357681.10	c.5C>T	p.Thr2Met	missense_variant	2/21	1	NM_001684.5	A1
ATP2B4	ENST00000341360.7	c.5C>T	p.Thr2Met	missense_variant	2/22	1		P4
ATP2B4	ENST00000705901.1	c.5C>T	p.Thr2Met	missense_variant	2/21

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000971 AC: 243 AN: 250326 Hom.: 0 AF XY: 0.000850 AC XY: 115 AN XY: 135234

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.000470 AC: 686 AN: 1460786 Hom.: 5 Cov.: 29 AF XY: 0.000454 AC XY: 330 AN XY: 726608

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.0173

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000801

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74446

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00110 Hom.: 5

Bravo AF: 0.000612

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.000491

EpiControl AF: 0.000178

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

Jul 15, 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

Jul 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;T;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	0.86	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.14
MVP		0.53
MPC		1.3
ClinPred		0.064	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140289832; hg19: chr1-203652338;