1-203683341-G-A

Position:

chr1-203683341-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001684.5(ATP2B4):c.136G>A(p.Val46Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,614,194 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0034 ( 19 hom. )

Consequence

ATP2B4
NM_001684.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.30

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003438145).

BP6

Variant 1-203683341-G-A is Benign according to our data. Variant chr1-203683341-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1584699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATP2B4	NM_001684.5 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant	2/21	ENST00000357681.10
ATP2B4	NM_001001396.3 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant	2/22
ATP2B4	NM_001365783.2 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant	2/21
ATP2B4	NM_001365784.2 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B4	ENST00000357681.10 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant	2/21	1	NM_001684.5	A1	P23634-6
ATP2B4	ENST00000341360.7 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant	2/22	1		P4	P23634-2
ATP2B4	ENST00000705901.1 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant	2/21				P23634-3

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00914

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00364

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00342

AC:

861

AN:

251446

Hom.:

AF XY:

0.00368

AC XY:

500

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00823

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00542

Gnomad FIN exome

AF:

0.00725

Gnomad NFE exome

AF:

0.00330

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00339

AC:

4963

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

2582

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00150

Gnomad4 ASJ exome

AF:

0.00823

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00501

Gnomad4 FIN exome

AF:

0.00650

Gnomad4 NFE exome

AF:

0.00331

Gnomad4 OTH exome

AF:

0.00329

GnomAD4 genome

AF:

0.00303

AC:

461

AN:

152314

Hom.:

Cov.:

AF XY:

0.00298

AC XY:

222

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00914

Gnomad4 NFE

AF:

0.00364

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00369

Hom.:

Bravo

AF:

0.00237

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00321

AC:

390

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00397

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ATP2B4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.45

T;T;.

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.81

L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.70

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.041

D;D;D

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.063

MVP

0.24

MPC

0.35

ClinPred

0.0045

GERP RS

0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.16

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