chr1-203683266-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001684.5(ATP2B4):​c.61G>A​(p.Asp21Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D21A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ATP2B4
NM_001684.5 missense

Scores

4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.47
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.25740808).
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP2B4NM_001684.5 linkuse as main transcriptc.61G>A p.Asp21Asn missense_variant 2/21 ENST00000357681.10
ATP2B4NM_001001396.3 linkuse as main transcriptc.61G>A p.Asp21Asn missense_variant 2/22
ATP2B4NM_001365783.2 linkuse as main transcriptc.61G>A p.Asp21Asn missense_variant 2/21
ATP2B4NM_001365784.2 linkuse as main transcriptc.61G>A p.Asp21Asn missense_variant 2/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP2B4ENST00000357681.10 linkuse as main transcriptc.61G>A p.Asp21Asn missense_variant 2/211 NM_001684.5 A1P23634-6
ATP2B4ENST00000341360.7 linkuse as main transcriptc.61G>A p.Asp21Asn missense_variant 2/221 P4P23634-2
ATP2B4ENST00000705901.1 linkuse as main transcriptc.61G>A p.Asp21Asn missense_variant 2/21 P23634-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461892
Hom.:
0
Cov.:
29
AF XY:
0.00000413
AC XY:
3
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 06, 2022The c.61G>A (p.D21N) alteration is located in exon 2 (coding exon 1) of the ATP2B4 gene. This alteration results from a G to A substitution at nucleotide position 61, causing the aspartic acid (D) at amino acid position 21 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.030
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
24
DANN
Uncertain
0.99
Eigen
Benign
0.013
Eigen_PC
Benign
0.097
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.91
D;D;.
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.26
T;T;T
MetaSVM
Uncertain
0.20
D
MutationAssessor
Benign
1.5
L;L;L
MutationTaster
Benign
0.98
D;D;D;D;D
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.1
N;N;N
REVEL
Benign
0.26
Sift
Benign
0.14
T;T;T
Sift4G
Benign
0.20
T;T;T
Polyphen
0.022
B;.;.
Vest4
0.17
MutPred
0.33
Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP
0.77
MPC
0.60
ClinPred
0.59
D
GERP RS
5.1
gMVP
0.47

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.

Other links and lift over

dbSNP: rs1030977850; hg19: chr1-203652394; API