chr16-84410569-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014861.4(ATP2C2):​c.419C>A​(p.Ala140Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ATP2C2
NM_014861.4 missense, splice_region

Scores

9
6
4
Splicing: ADA: 0.6221
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.33
Variant links:
Genes affected
ATP2C2 (HGNC:29103): (ATPase secretory pathway Ca2+ transporting 2) Enables P-type calcium transporter activity and P-type manganese transporter activity. Predicted to be involved in calcium ion transmembrane transport; cellular calcium ion homeostasis; and manganese ion transport. Predicted to act upstream of or within mammary gland epithelium development; positive regulation of calcium ion import; and protein localization to plasma membrane. Predicted to be located in trans-Golgi network membrane. Predicted to be active in Golgi membrane; endoplasmic reticulum; and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP2C2NM_014861.4 linkc.419C>A p.Ala140Glu missense_variant, splice_region_variant Exon 5 of 27 ENST00000262429.9 NP_055676.3 O75185-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP2C2ENST00000262429.9 linkc.419C>A p.Ala140Glu missense_variant, splice_region_variant Exon 5 of 27 1 NM_014861.4 ENSP00000262429.4 O75185-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 13, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.419C>A (p.A140E) alteration is located in exon 5 (coding exon 5) of the ATP2C2 gene. This alteration results from a C to A substitution at nucleotide position 419, causing the alanine (A) at amino acid position 140 to be replaced by a glutamic acid (E). 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
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.71
D;.
Eigen
Benign
0.084
Eigen_PC
Benign
0.066
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.062
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Uncertain
-0.061
T
MutationAssessor
Pathogenic
3.6
H;H
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-4.4
D;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;.
Vest4
0.86
MutPred
0.74
Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP
0.64
ClinPred
0.98
D
GERP RS
4.6
Varity_R
0.58
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.62
dbscSNV1_RF
Benign
0.60
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-84444175; API