12-89656726-A-G

Variant names:

• chr12-89656726-A-G
• rs12579302
• NM_001366521.1:c.-221-619T>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.-221-619T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,156 control chromosomes in the GnomAD database, including 2,091 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 (2091 hom., cov: 32)
• Consequence: ATP2B1 NM_001366521.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.371
• Publications: 19 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B1	NM_001366521.1	c.-221-619T>C		intron_variant	Intron 1 of 20	ENST00000428670.8	NP_001353450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2B1	ENST00000428670.8	c.-221-619T>C		intron_variant	Intron 1 of 20	5	NM_001366521.1	ENSP00000392043.3

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22942 AN: 152038 Hom.: 2085 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.0775

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: 0.151 AC: 22947 AN: 152156 Hom.: 2091 Cov.: 32 AF XY: 0.153 AC XY: 11347 AN XY: 74378

African (AFR) AF: 0.105 AC: 4361 AN: 41502

American (AMR) AF: 0.124 AC: 1890 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3466

East Asian (EAS) AF: 0.330 AC: 1707 AN: 5180

South Asian (SAS) AF: 0.357 AC: 1722 AN: 4820

European-Finnish (FIN) AF: 0.0775 AC: 821 AN: 10598

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

European-Non Finnish (NFE) AF: 0.164 AC: 11143 AN: 67988

Other (OTH) AF: 0.164 AC: 347 AN: 2112

Alfa AF: 0.135 Hom.: 439

Bravo AF: 0.149

Asia WGS AF: 0.258 AC: 900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.8
DANN	Benign	0.34
PhyloP100		0.37
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: rs12579302; hg19: chr12-90050503;