rs1594899

Variant names:

• chr3-10644374-G-A
• rs1594899
• NM_001438036.1:c.-459-24413C>T

Variant summary

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

The NM_001438036.1(ATP2B2):​c.-459-24413C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 152,236 control chromosomes in the GnomAD database, including 65 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 0.023 (65 hom., cov: 33)
• Consequence: ATP2B2 NM_001438036.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.369
• Publications: 1 publications found

Genes affected

ATP2B2 (HGNC:815): (ATPase plasma membrane Ca2+ transporting 2) 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 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B2 Gene-Disease associations (from GenCC):

• hearing loss, autosomal dominant 82

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B2	NM_001438036.1	c.-459-24413C>T		intron_variant	Intron 1 of 21		NP_001424965.1
ATP2B2	XM_005265179.6	c.-459-24413C>T		intron_variant	Intron 1 of 24		XP_005265236.1
ATP2B2	XM_006713175.5	c.-459-24413C>T		intron_variant	Intron 1 of 24		XP_006713238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2B2	ENST00000646379.1	c.-459-24413C>T		intron_variant	Intron 1 of 21			ENSP00000494381.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3489 AN: 152118 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0371

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.0312

Gnomad SAS AF: 0.0869

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0258

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

GnomAD4 genome AF: 0.0230 AC: 3496 AN: 152236 Hom.: 65 Cov.: 33 AF XY: 0.0248 AC XY: 1849 AN XY: 74436

African (AFR) AF: 0.00547 AC: 227 AN: 41536

American (AMR) AF: 0.0378 AC: 579 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3470

East Asian (EAS) AF: 0.0310 AC: 161 AN: 5188

South Asian (SAS) AF: 0.0867 AC: 418 AN: 4820

European-Finnish (FIN) AF: 0.0333 AC: 353 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1631 AN: 67998

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0232 Hom.: 8

Bravo AF: 0.0224

Asia WGS AF: 0.0550 AC: 190 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.7
DANN	Benign	0.80
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: rs1594899; hg19: chr3-10686059;