dbSNP rs146234576: ATP2B4:p.Arg7Ser (chr1-203683224-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -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. 13/20 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. R7H) 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

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 644 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001684.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2B4	NM_001684.5	MANE Select	c.19C>A	p.Arg7Ser	missense	Exon 2 of 21	NP_001675.3
ATP2B4	NM_001001396.3		c.19C>A	p.Arg7Ser	missense	Exon 2 of 22	NP_001001396.1	P23634-2
ATP2B4	NM_001365783.2		c.19C>A	p.Arg7Ser	missense	Exon 2 of 21	NP_001352712.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2B4	ENST00000357681.10	TSL:1 MANE Select	c.19C>A	p.Arg7Ser	missense	Exon 2 of 21	ENSP00000350310.5	P23634-6
ATP2B4	ENST00000341360.7	TSL:1	c.19C>A	p.Arg7Ser	missense	Exon 2 of 22	ENSP00000340930.2	P23634-2
ATP2B4	ENST00000890814.1		c.19C>A	p.Arg7Ser	missense	Exon 2 of 21	ENSP00000560873.1

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

GnomAD2 exomes

AF:

0.00561

AC:

1409

AN:

251060

AF XY:

0.00518

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 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

African (AFR)

AF:

0.000179

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0183

AC:

725

AN:

39696

South Asian (SAS)

AF:

0.000824

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.0330

AC:

1765

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000222

AC:

247

AN:

1111882

Other (OTH)

AF:

0.00444

AC:

268

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

155

310

466

621

776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00423

AC:

644

AN:

152262

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

464

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41542

American (AMR)

AF:

0.000850

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0222

AC:

115

AN:

5190

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0429

AC:

454

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68020

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00172

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

ATP2B4-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.34

PhyloP100

2.9

PrimateAI

Benign

0.22

PROVEAN

Benign

0.26

REVEL

Uncertain

0.31

Sift

Benign

0.66

Sift4G

Benign

0.61

Polyphen

0.017

Vest4

0.12

MVP

0.32

MPC

0.54

ClinPred

0.023

GERP RS

5.1

PromoterAI

-0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.35

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over