NM_001366521.1:c.-222+19464G>T

Variant names:

• chr12-89689132-C-A
• rs2037375
• NM_001366521.1:c.-222+19464G>T

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+19464G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 152,042 control chromosomes in the GnomAD database, including 61,706 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 0.90 (61706 hom., cov: 31)
• Consequence: ATP2B1 NM_001366521.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204
• Publications: 1 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B1	NM_001366521.1	c.-222+19464G>T		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.-222+19464G>T		intron_variant	Intron 1 of 20	5	NM_001366521.1	ENSP00000392043.3
ATP2B1	ENST00000359142.8	c.-222+19464G>T		intron_variant	Intron 1 of 21	5		ENSP00000352054.3
ATP2B1	ENST00000551310.2	c.-222+20087G>T		intron_variant	Intron 1 of 21	3		ENSP00000447041.2
ATP2B1	ENST00000705822.1	c.-222+20087G>T		intron_variant	Intron 1 of 21			ENSP00000516172.1

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136151 AN: 151924 Hom.: 61669 Cov.: 31

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.952

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.971

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.949

Gnomad OTH AF: 0.912

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

GnomAD4 genome AF: 0.896 AC: 136246 AN: 152042 Hom.: 61706 Cov.: 31 AF XY: 0.899 AC XY: 66859 AN XY: 74342

African (AFR) AF: 0.744 AC: 30839 AN: 41440

American (AMR) AF: 0.938 AC: 14304 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.952 AC: 3302 AN: 3468

East Asian (EAS) AF: 0.993 AC: 5132 AN: 5168

South Asian (SAS) AF: 0.981 AC: 4730 AN: 4820

European-Finnish (FIN) AF: 0.971 AC: 10301 AN: 10614

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.949 AC: 64524 AN: 67968

Other (OTH) AF: 0.913 AC: 1926 AN: 2110

Alfa AF: 0.920 Hom.: 10020

Bravo AF: 0.887

Asia WGS AF: 0.962 AC: 3345 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.3
DANN	Benign	0.61
PhyloP100		0.20
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: rs2037375; hg19: chr12-90082909;