1-203683224-C-T

Position:

chr1-203683224-C-T

Variant summary

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

The ENST00000357681.10(ATP2B4):c.19C>T(p.Arg7Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ATP2B4
ENST00000357681.10 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044196546).

BP6

Variant 1-203683224-C-T is Benign according to our data. Variant chr1-203683224-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 703903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 150 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATP2B4	NM_001684.5 linkuse as main transcript	c.19C>T	p.Arg7Cys	missense_variant	2/21	ENST00000357681.10	NP_001675.3
ATP2B4	NM_001001396.3 linkuse as main transcript	c.19C>T	p.Arg7Cys	missense_variant	2/22		NP_001001396.1
ATP2B4	NM_001365783.2 linkuse as main transcript	c.19C>T	p.Arg7Cys	missense_variant	2/21		NP_001352712.1
ATP2B4	NM_001365784.2 linkuse as main transcript	c.19C>T	p.Arg7Cys	missense_variant	2/21		NP_001352713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2B4	ENST00000357681.10 linkuse as main transcript	c.19C>T	p.Arg7Cys	missense_variant	2/21	1	NM_001684.5	ENSP00000350310	A1	P23634-6
ATP2B4	ENST00000341360.7 linkuse as main transcript	c.19C>T	p.Arg7Cys	missense_variant	2/22	1		ENSP00000340930	P4	P23634-2
ATP2B4	ENST00000705901.1 linkuse as main transcript	c.19C>T	p.Arg7Cys	missense_variant	2/21			ENSP00000516177		P23634-3

Frequencies

GnomAD3 genomes

AF:

0.000960

AC:

146

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000319

AC:

AN:

251060

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1461648

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00335

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000985

AC:

150

AN:

152262

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00339

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000115

Hom.:

Bravo

AF:

0.00109

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 24, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.92

D;D;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Uncertain

-0.035

MutationAssessor

Benign

0.34

N;N;N

MutationTaster

Benign

0.69

D;D;D;D;D

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.74

N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.90

P;.;.

Vest4

0.14

MVP

0.47

MPC

1.2

ClinPred

0.017

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.37

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