16-84398538-A-T

Variant names:

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

Variant summary

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

The NM_014861.4(ATP2C2):​c.139A>T​(p.Lys47*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ATP2C2 NM_014861.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2C2	NM_014861.4	c.139A>T	p.Lys47*	stop_gained	Exon 2 of 27	ENST00000262429.9	NP_055676.3
ATP2C2	NM_001286527.3	c.139A>T	p.Lys47*	stop_gained	Exon 2 of 28		NP_001273456.2
ATP2C2	XM_011523486.3	c.70A>T	p.Lys24*	stop_gained	Exon 2 of 28		XP_011521788.1
ATP2C2	XM_047434994.1	c.70A>T	p.Lys24*	stop_gained	Exon 2 of 27		XP_047290950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2C2	ENST00000262429.9	c.139A>T	p.Lys47*	stop_gained	Exon 2 of 27	1	NM_014861.4	ENSP00000262429.4
ATP2C2	ENST00000416219.7	c.139A>T	p.Lys47*	stop_gained	Exon 2 of 28	1		ENSP00000397925.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000263 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.63	D
PhyloP100		2.6
Vest4		0.37
GERP RS		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369571363; hg19: chr16-84432144;