rs78887288

chr16-84405221-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014861.4(ATP2C2):c.304G>A(p.Val102Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,614,018 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (38 hom.)
• Consequence: ATP2C2 NM_014861.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.948

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024264753).
• BP6: Variant 16-84405221-G-A is Benign according to our data. Variant chr16-84405221-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547871.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2C2	NM_014861.4	c.304G>A	p.Val102Met	missense_variant	3/27	ENST00000262429.9
ATP2C2	NM_001286527.3	c.304G>A	p.Val102Met	missense_variant	3/28
ATP2C2	XM_011523486.3	c.235G>A	p.Val79Met	missense_variant	3/28
ATP2C2	XM_047434994.1	c.235G>A	p.Val79Met	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2C2	ENST00000262429.9	c.304G>A	p.Val102Met	missense_variant	3/27	1	NM_014861.4	P1
ATP2C2	ENST00000416219.6	c.304G>A	p.Val102Met	missense_variant	3/28	1
ATP2C2	ENST00000565631.5	n.795G>A		non_coding_transcript_exon_variant	1/25	2
ATP2C2	ENST00000569207.5	c.4G>A	p.Val2Met	missense_variant, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 709 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00481 AC: 1199 AN: 249070 Hom.: 5 AF XY: 0.00470 AC XY: 635 AN XY: 135102

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00344

Gnomad NFE exome AF: 0.00754

Gnomad OTH exome AF: 0.00463

GnomAD4 exome AF: 0.00636 AC: 9299 AN: 1461706 Hom.: 38 Cov.: 31 AF XY: 0.00623 AC XY: 4528 AN XY: 727152

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.00743

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.00465 AC: 709 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00422 AC XY: 314 AN XY: 74460

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00764

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00699 Hom.: 11

Bravo AF: 0.00463

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00170 AC: 7

ESP6500EA AF: 0.00665 AC: 56

ExAC AF: 0.00465 AC: 563

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00676

EpiControl AF: 0.00652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ATP2C2: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 30, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	13
Dann	Benign	0.96
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.12
Sift	Benign	0.079	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.011	B;.
Vest4		0.32
MVP		0.42
ClinPred		0.0043	T
GERP RS		2.0
Varity_R		0.021
gMVP		0.31

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

Other links and lift over

dbSNP: rs78887288; hg19: chr16-84438827;