NM_001353564.1:c.-320+1756T>C

Variant names:

• chr3-10532283-A-G
• rs6442177
• NM_001353564.1:c.-320+1756T>C

Variant summary

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

The NM_001353564.1(ATP2B2):​c.-320+1756T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,074 control chromosomes in the GnomAD database, including 10,428 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 0.37 (10428 hom., cov: 32)
• Consequence: ATP2B2 NM_001353564.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.124
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B2	NM_001353564.1	c.-320+1756T>C		intron_variant	Intron 2 of 20		NP_001340493.1
ATP2B2	NM_001438036.1	c.-320+1756T>C		intron_variant	Intron 3 of 21		NP_001424965.1
ATP2B2	XM_005265179.6	c.-320+1756T>C		intron_variant	Intron 3 of 24		XP_005265236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2B2	ENST00000646379.1	c.-320+1756T>C		intron_variant	Intron 3 of 21			ENSP00000494381.1
ATP2B2	ENST00000460129.5	n.-320+1756T>C		intron_variant	Intron 1 of 21	5		ENSP00000424494.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55531 AN: 151956 Hom.: 10422 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.365 AC: 55562 AN: 152074 Hom.: 10428 Cov.: 32 AF XY: 0.368 AC XY: 27351 AN XY: 74332

African (AFR) AF: 0.323 AC: 13389 AN: 41480

American (AMR) AF: 0.311 AC: 4757 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1137 AN: 3470

East Asian (EAS) AF: 0.218 AC: 1129 AN: 5176

South Asian (SAS) AF: 0.462 AC: 2216 AN: 4800

European-Finnish (FIN) AF: 0.454 AC: 4796 AN: 10574

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26977 AN: 67974

Other (OTH) AF: 0.371 AC: 785 AN: 2114

Alfa AF: 0.383 Hom.: 36684

Bravo AF: 0.352

Asia WGS AF: 0.325 AC: 1128 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.43
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: rs6442177; hg19: chr3-10573967;