rs771763620

Variant names:

• chr16-84459342-G-C
• rs771763620
• NM_014861.4:c.2289G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014861.4(ATP2C2):​c.2289G>C​(p.Gln763His) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,870 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: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ATP2C2 NM_014861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.68

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]

ATP2C2-AS1 (HGNC:53167): (ATP2C2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2C2	NM_014861.4	c.2289G>C	p.Gln763His	missense_variant	Exon 23 of 27	ENST00000262429.9	NP_055676.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2C2	ENST00000262429.9	c.2289G>C	p.Gln763His	missense_variant	Exon 23 of 27	1	NM_014861.4	ENSP00000262429.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249540 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461870 Hom.: 0 Cov.: 36 AF XY: 0.0000138 AC XY: 10 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2289G>C (p.Q763H) alteration is located in exon 23 (coding exon 23) of the ATP2C2 gene. This alteration results from a G to C substitution at nucleotide position 2289, causing the glutamine (Q) at amino acid position 763 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.92		Loss of catalytic residue at Q763 (P = 0.1352);Loss of catalytic residue at Q763 (P = 0.1352);
MVP		0.92
ClinPred		0.95	D
GERP RS		3.7
Varity_R		0.36
gMVP		0.92

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: rs771763620; hg19: chr16-84492948;