3-10329020-C-G

Position:

• chr3-10329020-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001001331.4(ATP2B2):​c.3526G>C​(p.Glu1176Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ATP2B2 NM_001001331.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

Genes affected

ATP2B2 (HGNC:815): (ATPase plasma membrane Ca2+ transporting 2) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP2B2. . Gene score misZ 4.5484 (greater than the threshold 3.09). Trascript score misZ 6.2948 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive nonsyndromic hearing loss 12, hearing loss, autosomal dominant 82.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41242692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2B2	NM_001001331.4	c.3526G>C	p.Glu1176Gln	missense_variant	23/23	ENST00000360273.7	NP_001001331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2B2	ENST00000360273.7	c.3526G>C	p.Glu1176Gln	missense_variant	23/23	5	NM_001001331.4	ENSP00000353414.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.3391G>C (p.E1131Q) alteration is located in exon 20 (coding exon 19) of the ATP2B2 gene. This alteration results from a G to C substitution at nucleotide position 3391, causing the glutamic acid (E) at amino acid position 1131 to be replaced by a glutamine (Q). 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	Benign	0.27
BayesDel_addAF	Benign	-0.0078	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;.;.;.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;.;D;D;D;.
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Benign	2.0	.;M;.;.;.;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.75	N;N;N;.;.;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.049	D;T;D;.;.;.;.
Sift4G	Benign	0.18	T;T;T;.;.;.;.
Polyphen		0.79	.;P;.;.;.;.;P
Vest4		0.30
MutPred		0.20		.;Loss of sheet (P = 0.0817);.;.;.;.;Loss of sheet (P = 0.0817);
MVP		0.44
MPC		2.3
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.15
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10370704;