16-84408489-G-A

Position:

• chr16-84408489-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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

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 -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 id 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. gnomad4_exome 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 gnomad4_exome. There are 2604 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2C2	NM_014861.4	c.412G>A	p.Ala138Thr	missense_variant	4/27	ENST00000262429.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2C2	ENST00000262429.9	c.412G>A	p.Ala138Thr	missense_variant	4/27	1	NM_014861.4	P1

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

GnomAD3 exomes AF: 0.00589 AC: 1459 AN: 247790 Hom.: 10 AF XY: 0.00499 AC XY: 672 AN XY: 134580

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 SAS exome AF: 0.000392

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

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00960

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00355

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

Gnomad4 AFR AF: 0.00285

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00389

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00796

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00335 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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.080	N;N
MutationTaster	Benign	0.65	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.2	N;N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;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

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: rs78371901; hg19: chr16-84442095; COSMIC: COSV52293436;