chr1-203683224-C-A

Position:

chr1-203683224-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.93

Variant links:

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]

ATP2B4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

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_single_submitter, 1 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 GnomAd4 at 644 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B4	ENST00000357681.10 linkuse as main transcript	c.19C>A	p.Arg7Ser	missense_variant	2/21	1	NM_001684.5	A1	P23634-6
ATP2B4	ENST00000341360.7 linkuse as main transcript	c.19C>A	p.Arg7Ser	missense_variant	2/22	1		P4	P23634-2
ATP2B4	ENST00000705901.1 linkuse as main transcript	c.19C>A	p.Arg7Ser	missense_variant	2/21				P23634-3

Frequencies

GnomAD3 genomes

AF:

0.00422

AC:

642

AN:

152144

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00518

AC XY:

703

AN XY:

135670

show subpopulations

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.:

Cov.:

AF XY:

0.00196

AC XY:

1426

AN XY:

727134

show subpopulations

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.:

Cov.:

AF XY:

0.00623

AC XY:

464

AN XY:

74432

show subpopulations

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.:

Bravo

AF:

0.00128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00486

AC:

590

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ATP2B4-related disorder

Benign:1

Benign, no assertion criteria provided

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.84

T;T;.

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.34

N;N;N

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Benign

0.22

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over