16-84398513-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014861.4(ATP2C2):c.114T>G(p.Ser38Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. S38N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ATP2C2
NM_014861.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.705

Publications

0 publications found

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]

ATP2C2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047713995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2C2	NM_014861.4 link	c.114T>G	p.Ser38Arg	missense_variant	Exon 2 of 27	ENST00000262429.9	NP_055676.3	O75185-1
ATP2C2	NM_001286527.3 link	c.114T>G	p.Ser38Arg	missense_variant	Exon 2 of 28		NP_001273456.2	O75185-3
ATP2C2	XM_011523486.3 link	c.45T>G	p.Ser15Arg	missense_variant	Exon 2 of 28		XP_011521788.1
ATP2C2	XM_047434994.1 link	c.45T>G	p.Ser15Arg	missense_variant	Exon 2 of 27		XP_047290950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2C2	ENST00000262429.9 link	c.114T>G	p.Ser38Arg	missense_variant	Exon 2 of 27	1	NM_014861.4	ENSP00000262429.4		O75185-1
ATP2C2	ENST00000416219.7 link	c.114T>G	p.Ser38Arg	missense_variant	Exon 2 of 28	1		ENSP00000397925.2		O75185-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457398

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725258

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000303

AC:

AN:

33022

American (AMR)

AF:

0.00

AC:

AN:

43686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39436

South Asian (SAS)

AF:

0.00

AC:

AN:

85796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110274

Other (OTH)

AF:

0.00

AC:

AN:

60136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000047), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 04, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.114T>G (p.S38R) alteration is located in exon 2 (coding exon 2) of the ATP2C2 gene. This alteration results from a T to G substitution at nucleotide position 114, causing the serine (S) at amino acid position 38 to be replaced by an arginine (R). 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

Benign

0.098

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.33

CADD

Benign

0.24

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0078

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.24

T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.34

N;N

PhyloP100

-0.70

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.75

N;N

REVEL

Benign

0.22

Sift

Benign

0.49

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.032

B;.

Vest4

0.15

MutPred

0.28

Loss of phosphorylation at S38 (P = 0.0231);Loss of phosphorylation at S38 (P = 0.0231);

MVP

0.22

ClinPred

0.12

GERP RS

-3.0

Varity_R

0.27

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

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

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16-84398513-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over