16-84410572-T-G

Variant names:

• chr16-84410572-T-G
• rs757440301
• NM_014861.4:c.422T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_014861.4(ATP2C2):​c.422T>G​(p.Val141Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,614,028 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ATP2C2 NM_014861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.40
• 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

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.422T>G	p.Val141Gly	missense	Exon 5 of 27	NP_055676.3	O75185-1
	ATP2C2	NM_001286527.3		c.422T>G	p.Val141Gly	missense	Exon 5 of 28	NP_001273456.2	O75185-3
	ATP2C2	NM_001291454.2		c.31T>G	p.Cys11Gly	missense	Exon 3 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.422T>G	p.Val141Gly	missense	Exon 5 of 27	ENSP00000262429.4	O75185-1
	ATP2C2	ENST00000416219.7	TSL:1	c.422T>G	p.Val141Gly	missense	Exon 5 of 28	ENSP00000397925.2
	ATP2C2	ENST00000861763.1		c.422T>G	p.Val141Gly	missense	Exon 5 of 28	ENSP00000531822.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249560 AF XY: 0.00000739

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.00000684 AC: 10 AN: 1461732 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727152

African (AFR) AF: 0.000269 AC: 9 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111948

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74468

African (AFR) AF: 0.000265 AC: 11 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000413 AC: 5

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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.67
MVP		0.84
ClinPred		0.63	D
GERP RS		4.6
Varity_R		0.29
gMVP		0.84
Mutation Taster		=76/24	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: rs757440301; hg19: chr16-84444178;