12-89615182-A-G

Variant names:

• chr12-89615182-A-G
• rs2681472
• NM_001366521.1:c.2067+1620T>C

Variant summary

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

The NM_001366521.1(ATP2B1):​c.2067+1620T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 152,102 control chromosomes in the GnomAD database, including 2,076 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 0.15 (2076 hom., cov: 32)
• Consequence: ATP2B1 NM_001366521.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• Publications: 148 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=-0.86).
• 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.2067+1620T>C		intron	N/A	NP_001353450.1	P20020-3
	ATP2B1	NM_001366524.1		c.2067+1620T>C		intron	N/A	NP_001353453.1	P20020-4
	ATP2B1	NM_001366525.1		c.2067+1620T>C		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.2067+1620T>C		intron	N/A	ENSP00000392043.3	P20020-3
	ATP2B1	ENST00000960959.1		c.2067+1620T>C		intron	N/A	ENSP00000631018.1
	ATP2B1	ENST00000960960.1		c.2067+1620T>C		intron	N/A	ENSP00000631019.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22754 AN: 151984 Hom.: 2071 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.162

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

GnomAD4 genome AF: 0.150 AC: 22758 AN: 152102 Hom.: 2076 Cov.: 32 AF XY: 0.151 AC XY: 11261 AN XY: 74360

African (AFR) AF: 0.102 AC: 4250 AN: 41486

American (AMR) AF: 0.123 AC: 1886 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3470

East Asian (EAS) AF: 0.330 AC: 1707 AN: 5174

South Asian (SAS) AF: 0.353 AC: 1699 AN: 4812

European-Finnish (FIN) AF: 0.0766 AC: 812 AN: 10600

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11096 AN: 67968

Other (OTH) AF: 0.161 AC: 341 AN: 2114

Alfa AF: 0.170 Hom.: 11171

Bravo AF: 0.148

Asia WGS AF: 0.256 AC: 894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.1
DANN	Benign	0.57
PhyloP100		-0.19
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: rs2681472; hg19: chr12-90008959;