12-89680664-G-C

Variant names:

• chr12-89680664-G-C
• rs11105368
• NM_001366521.1:c.-221-24557C>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.-221-24557C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,050 control chromosomes in the GnomAD database, including 2,148 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 (2148 hom., cov: 32)
• Consequence: ATP2B1 NM_001366521.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 16 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B1	NM_001366521.1	MANE Select	c.-221-24557C>G		intron	N/A	NP_001353450.1
	ATP2B1	NM_001366524.1		c.-221-24557C>G		intron	N/A	NP_001353453.1
	ATP2B1	NM_001366525.1		c.-221-24557C>G		intron	N/A	NP_001353454.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B1	ENST00000428670.8	TSL:5 MANE Select	c.-221-24557C>G		intron	N/A	ENSP00000392043.3
	ATP2B1	ENST00000359142.8	TSL:5	c.-221-24557C>G		intron	N/A	ENSP00000352054.3
	ATP2B1	ENST00000551310.2	TSL:3	c.-221-24557C>G		intron	N/A	ENSP00000447041.2

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23343 AN: 151930 Hom.: 2141 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.154 AC: 23356 AN: 152050 Hom.: 2148 Cov.: 32 AF XY: 0.155 AC XY: 11554 AN XY: 74346

African (AFR) AF: 0.115 AC: 4772 AN: 41484

American (AMR) AF: 0.125 AC: 1909 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 826 AN: 3466

East Asian (EAS) AF: 0.330 AC: 1708 AN: 5176

South Asian (SAS) AF: 0.357 AC: 1723 AN: 4822

European-Finnish (FIN) AF: 0.0776 AC: 819 AN: 10558

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

European-Non Finnish (NFE) AF: 0.164 AC: 11120 AN: 67950

Other (OTH) AF: 0.164 AC: 346 AN: 2106

Alfa AF: 0.0728 Hom.: 77

Bravo AF: 0.152

Asia WGS AF: 0.261 AC: 909 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.5
DANN	Benign	0.72
PhyloP100		0.12
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: rs11105368; hg19: chr12-90074441;