chr1-203698330-C-T

Variant summary

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

The NM_001684.5(ATP2B4):​c.367C>T​(p.Arg123Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R123H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

ATP2B4
NM_001684.5 missense

Scores

4
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.25
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=0.24688679).
BS2
High AC in GnomAdExome4 at 106 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP2B4NM_001684.5 linkuse as main transcriptc.367C>T p.Arg123Cys missense_variant 3/21 ENST00000357681.10
ATP2B4NM_001001396.3 linkuse as main transcriptc.367C>T p.Arg123Cys missense_variant 3/22
ATP2B4NM_001365783.2 linkuse as main transcriptc.367C>T p.Arg123Cys missense_variant 3/21
ATP2B4NM_001365784.2 linkuse as main transcriptc.367C>T p.Arg123Cys missense_variant 3/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP2B4ENST00000357681.10 linkuse as main transcriptc.367C>T p.Arg123Cys missense_variant 3/211 NM_001684.5 A1P23634-6
ATP2B4ENST00000341360.7 linkuse as main transcriptc.367C>T p.Arg123Cys missense_variant 3/221 P4P23634-2
ATP2B4ENST00000705901.1 linkuse as main transcriptc.367C>T p.Arg123Cys missense_variant 3/21 P23634-3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152106
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000127
AC:
32
AN:
251414
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000882
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000725
AC:
106
AN:
1461870
Hom.:
0
Cov.:
35
AF XY:
0.0000839
AC XY:
61
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000754
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152224
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000988
AC:
12

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 13, 2023The c.367C>T (p.R123C) alteration is located in exon 3 (coding exon 2) of the ATP2B4 gene. This alteration results from a C to T substitution at nucleotide position 367, causing the arginine (R) at amino acid position 123 to be replaced by a cysteine (C). 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
-0.11
T
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
32
DANN
Pathogenic
1.0
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;.
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.25
T;T;T
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Uncertain
2.1
M;M;M
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-3.4
D;D;D
REVEL
Uncertain
0.50
Sift
Uncertain
0.018
D;D;D
Sift4G
Uncertain
0.050
T;T;T
Polyphen
1.0
D;.;.
Vest4
0.45
MVP
0.63
MPC
1.4
ClinPred
0.63
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
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: rs779601653; hg19: chr1-203667458; COSMIC: COSV58175453; API