12-89687411-T-C

Variant names:

• chr12-89687411-T-C
• rs7136259
• NM_001366521.1:c.-222+21185A>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.-222+21185A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 151,952 control chromosomes in the GnomAD database, including 26,580 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 0.59 (26580 hom., cov: 32)
• Consequence: ATP2B1 NM_001366521.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.213
• Publications: 60 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: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.674 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.-222+21185A>G		intron	N/A	NP_001353450.1
	ATP2B1	NM_001366524.1		c.-222+21808A>G		intron	N/A	NP_001353453.1
	ATP2B1	NM_001366525.1		c.-222+21185A>G		intron	N/A	NP_001353454.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B1	ENST00000428670.8	TSL:5 MANE Select	c.-222+21185A>G		intron	N/A	ENSP00000392043.3
	ATP2B1	ENST00000960959.1		c.-222+21808A>G		intron	N/A	ENSP00000631018.1
	ATP2B1	ENST00000960960.1		c.-222+21185A>G		intron	N/A	ENSP00000631019.1

Frequencies

GnomAD3 genomes AF: 0.586 AC: 89040 AN: 151834 Hom.: 26551 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.586 AC: 89099 AN: 151952 Hom.: 26580 Cov.: 32 AF XY: 0.590 AC XY: 43855 AN XY: 74270

African (AFR) AF: 0.517 AC: 21416 AN: 41428

American (AMR) AF: 0.685 AC: 10443 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1869 AN: 3470

East Asian (EAS) AF: 0.636 AC: 3296 AN: 5182

South Asian (SAS) AF: 0.534 AC: 2578 AN: 4832

European-Finnish (FIN) AF: 0.715 AC: 7558 AN: 10574

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.589 AC: 40007 AN: 67908

Other (OTH) AF: 0.588 AC: 1240 AN: 2110

Alfa AF: 0.585 Hom.: 104091

Bravo AF: 0.583

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.9
DANN	Benign	0.46
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7136259; hg19: chr12-90081188;