chr12-89619312-T-C

Variant names:

• chr12-89619312-T-C
• rs2681492
• NM_001366521.1:c.1829+687A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001366521.1(ATP2B1):​c.1829+687A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,072 control chromosomes in the GnomAD database, including 2,179 homozygotes. 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: 𝑓 0.16 (2179 hom., cov: 31)
• Consequence: ATP2B1 NM_001366521.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.450
• Publications: 95 publications found

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]

ATP2B1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal dominant 66

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366521.1. 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
	ATP2B1	NM_001366521.1	MANE Select	c.1829+687A>G		intron	N/A	NP_001353450.1	P20020-3
	ATP2B1	NM_001366524.1		c.1829+687A>G		intron	N/A	NP_001353453.1	P20020-4
	ATP2B1	NM_001366525.1		c.1829+687A>G		intron	N/A	NP_001353454.1	P20020-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B1	ENST00000428670.8	TSL:5 MANE Select	c.1829+687A>G		intron	N/A	ENSP00000392043.3	P20020-3
	ATP2B1	ENST00000960959.1		c.1829+687A>G		intron	N/A	ENSP00000631018.1
	ATP2B1	ENST00000960960.1		c.1829+687A>G		intron	N/A	ENSP00000631019.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23625 AN: 151954 Hom.: 2173 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.0769

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.167

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.155 AC: 23635 AN: 152072 Hom.: 2179 Cov.: 31 AF XY: 0.157 AC XY: 11668 AN XY: 74322

African (AFR) AF: 0.122 AC: 5060 AN: 41508

American (AMR) AF: 0.126 AC: 1924 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 835 AN: 3472

East Asian (EAS) AF: 0.330 AC: 1701 AN: 5154

South Asian (SAS) AF: 0.353 AC: 1696 AN: 4810

European-Finnish (FIN) AF: 0.0769 AC: 813 AN: 10570

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11121 AN: 67978

Other (OTH) AF: 0.166 AC: 351 AN: 2112

Alfa AF: 0.168 Hom.: 9504

Bravo AF: 0.154

Asia WGS AF: 0.258 AC: 900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.49
DANN	Benign	0.39
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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: rs2681492; hg19: chr12-90013089;