16-84398538-A-G

Variant names:

• chr16-84398538-A-G
• rs369571363
• NM_014861.4:c.139A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014861.4(ATP2C2):​c.139A>G​(p.Lys47Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ATP2C2 NM_014861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08535129).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014861.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C2	NM_014861.4	MANE Select	c.139A>G	p.Lys47Glu	missense	Exon 2 of 27	NP_055676.3	O75185-1
	ATP2C2	NM_001286527.3		c.139A>G	p.Lys47Glu	missense	Exon 2 of 28	NP_001273456.2	O75185-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C2	ENST00000262429.9	TSL:1 MANE Select	c.139A>G	p.Lys47Glu	missense	Exon 2 of 27	ENSP00000262429.4	O75185-1
	ATP2C2	ENST00000416219.7	TSL:1	c.139A>G	p.Lys47Glu	missense	Exon 2 of 28	ENSP00000397925.2
	ATP2C2	ENST00000861763.1		c.139A>G	p.Lys47Glu	missense	Exon 2 of 28	ENSP00000531822.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461248 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726940

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111772

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.28
Sift	Benign	0.43	T
Sift4G	Benign	0.58	T
Polyphen		0.077	B
Vest4		0.43
MutPred		0.25		Loss of ubiquitination at K47 (P = 0.0141)
MVP		0.71
ClinPred		0.53	D
GERP RS		2.8
Varity_R		0.28
gMVP		0.46
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs369571363; hg19: chr16-84432144;