16-84398569-C-T

Variant names:

• chr16-84398569-C-T
• rs780617194
• NM_014861.4:c.170C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014861.4(ATP2C2):​c.170C>T​(p.Ala57Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000582 in 1,460,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A57A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: ATP2C2 NM_014861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2C2	NM_014861.4	c.170C>T	p.Ala57Val	missense_variant	Exon 2 of 27	ENST00000262429.9	NP_055676.3
ATP2C2	NM_001286527.3	c.170C>T	p.Ala57Val	missense_variant	Exon 2 of 28		NP_001273456.2
ATP2C2	XM_011523486.3	c.101C>T	p.Ala34Val	missense_variant	Exon 2 of 28		XP_011521788.1
ATP2C2	XM_047434994.1	c.101C>T	p.Ala34Val	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	c.170C>T	p.Ala57Val	missense_variant	Exon 2 of 27	1	NM_014861.4	ENSP00000262429.4
ATP2C2	ENST00000416219.7	c.170C>T	p.Ala57Val	missense_variant	Exon 2 of 28	1		ENSP00000397925.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248198 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000582 AC: 85 AN: 1460674 Hom.: 0 Cov.: 30 AF XY: 0.0000578 AC XY: 42 AN XY: 726698

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111484

Other (OTH) AF: 0.0000166 AC: 1 AN: 60348

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000546

EpiControl AF: 0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.170C>T (p.A57V) alteration is located in exon 2 (coding exon 2) of the ATP2C2 gene. This alteration results from a C to T substitution at nucleotide position 170, causing the alanine (A) at amino acid position 57 to be replaced by a valine (V). 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	0.30
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.066	D
MutationAssessor	Benign	1.0	L;L
PhyloP100		5.0
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.51
Sift	Benign	0.14	T;T
Sift4G	Benign	0.33	T;T
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.68		Loss of ubiquitination at K59 (P = 0.0327);Loss of ubiquitination at K59 (P = 0.0327);
MVP		0.71
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.45
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs780617194; hg19: chr16-84432175; COSMIC: COSV52297485;