16-84408489-G-A

Variant names:

• chr16-84408489-G-A
• rs78371901
• NM_014861.4:c.412G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014861.4(ATP2C2):​c.412G>A​(p.Ala138Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,612,442 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (28 hom.)
• Consequence: ATP2C2 NM_014861.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.240
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009264618).
• BP6: Variant 16-84408489-G-A is Benign according to our data. Variant chr16-84408489-G-A is described in ClinVar as Benign. ClinVar VariationId is 779452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00384 (5603/1460446) while in subpopulation AMR AF = 0.0178 (798/44718). AF 95% confidence interval is 0.0168. There are 28 homozygotes in GnomAdExome4. There are 2604 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.412G>A	p.Ala138Thr	missense	Exon 4 of 27	NP_055676.3	O75185-1
	ATP2C2	NM_001286527.3		c.412G>A	p.Ala138Thr	missense	Exon 4 of 28	NP_001273456.2	O75185-3
	ATP2C2	NM_001291454.2		c.21G>A	p.Ser7Ser	synonymous	Exon 2 of 24	NP_001278383.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C2	ENST00000262429.9	TSL:1 MANE Select	c.412G>A	p.Ala138Thr	missense	Exon 4 of 27	ENSP00000262429.4	O75185-1
	ATP2C2	ENST00000416219.7	TSL:1	c.412G>A	p.Ala138Thr	missense	Exon 4 of 28	ENSP00000397925.2
	ATP2C2	ENST00000861763.1		c.412G>A	p.Ala138Thr	missense	Exon 4 of 28	ENSP00000531822.1

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 538 AN: 151878 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00796

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00589 AC: 1459 AN: 247790 AF XY: 0.00499

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00723

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00563

GnomAD4 exome AF: 0.00384 AC: 5603 AN: 1460446 Hom.: 28 Cov.: 31 AF XY: 0.00358 AC XY: 2604 AN XY: 726528

African (AFR) AF: 0.00206 AC: 69 AN: 33474

American (AMR) AF: 0.0178 AC: 798 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26132

East Asian (EAS) AF: 0.00164 AC: 65 AN: 39696

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86238

European-Finnish (FIN) AF: 0.00960 AC: 502 AN: 52282

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00349 AC: 3877 AN: 1111778

Other (OTH) AF: 0.00355 AC: 214 AN: 60362

GnomAD4 genome AF: 0.00357 AC: 543 AN: 151996 Hom.: 3 Cov.: 31 AF XY: 0.00342 AC XY: 254 AN XY: 74282

African (AFR) AF: 0.00285 AC: 118 AN: 41446

American (AMR) AF: 0.00537 AC: 82 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00389 AC: 20 AN: 5140

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00796 AC: 84 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00332 AC: 226 AN: 67984

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00305 Hom.: 5

Bravo AF: 0.00376

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00287 AC: 12

ESP6500EA AF: 0.00355 AC: 30

ExAC AF: 0.00596 AC: 722

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.00278

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	0.34
DANN	Benign	0.34
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.080	N
PhyloP100		-0.24
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.2	N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.35
MVP		0.28
ClinPred		0.00024	T
GERP RS		-0.14
Varity_R		0.044
gMVP		0.55
Mutation Taster		=73/27	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: rs78371901; hg19: chr16-84442095; COSMIC: COSV52293436;