12-89591072-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001366521.1(ATP2B1):​c.3575G>T​(p.Ser1192Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ATP2B1
NM_001366521.1 missense

Scores

8
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.89
Variant links:
Genes affected
ATP2B1 (HGNC:814): (ATPase plasma membrane Ca2+ transporting 1) 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 1. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP2B1NM_001366521.1 linkc.3575G>T p.Ser1192Ile missense_variant Exon 21 of 21 ENST00000428670.8 NP_001353450.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP2B1ENST00000428670.8 linkc.3575G>T p.Ser1192Ile missense_variant Exon 21 of 21 5 NM_001366521.1 ENSP00000392043.3 P20020-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

Intellectual developmental disorder, autosomal dominant 66 Uncertain:1
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PP3+PP2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.027
.;.;T
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
D;.;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Uncertain
0.45
T;T;T
MetaSVM
Pathogenic
0.95
D
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.6
N;N;N
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0050
D;D;D
Sift4G
Uncertain
0.0090
D;D;D
Vest4
0.56
MutPred
0.30
Gain of catalytic residue at D1191 (P = 0.0024);Gain of catalytic residue at D1191 (P = 0.0024);.;
MVP
0.79
MPC
0.14
ClinPred
0.98
D
GERP RS
5.5
Varity_R
0.41
gMVP
0.64

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: rs1804194; hg19: chr12-89984849; API