12-89603165-C-A

Position:

• chr12-89603165-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001366521.1(ATP2B1):​c.2938G>T​(p.Val980Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2B1 NM_001366521.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

Genes affected

ATP2B1 (HGNC:814): (ATPase plasma membrane Ca2+ transporting 1) 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 1. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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), ATP2B1. . Gene score misZ 5.2916 (greater than the threshold 3.09). Trascript score misZ 6.9991 (greater than threshold 3.09). GenCC has associacion of gene with intellectual developmental disorder, autosomal dominant 66.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 12-89603165-C-A is Pathogenic according to our data. Variant chr12-89603165-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1334403.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B1	NM_001366521.1	c.2938G>T	p.Val980Leu	missense_variant	18/21	ENST00000428670.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B1	ENST00000428670.8	c.2938G>T	p.Val980Leu	missense_variant	18/21	5	NM_001366521.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Clubfoot;C0020598:Hypocalcemia;C0031900:Isolated Pierre-Robin syndrome;C1868720:Periventricular nodular heterotopia;C4022738:Neurodevelopmental delay Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Kids Research, The Children's Hospital at Westmead

Jan 12, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.79
MutPred		0.70		Gain of catalytic residue at V975 (P = 0.0037);Gain of catalytic residue at V975 (P = 0.0037);Gain of catalytic residue at V975 (P = 0.0037);.;
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.74
gMVP		0.98

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: rs370810713; hg19: chr12-89996942;