chr3-10449546-T-C

Variant names:

• chr3-10449546-T-C
• rs9826066
• ENST00000480680.2:n.437A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000480680.2(ATP2B2):​n.437A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,614,214 control chromosomes in the GnomAD database, including 1,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (768 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (725 hom.)
• Consequence: ATP2B2 ENST00000480680.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.103
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-10449546-T-C is Benign according to our data. Variant chr3-10449546-T-C is described in ClinVar as Benign. ClinVar VariationId is 585335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000480680.2. 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
	ATP2B2	NM_001001331.4	MANE Select	c.-3A>G		5_prime_UTR	Exon 2 of 23	NP_001001331.1
	ATP2B2	NM_001438646.1		c.-3A>G		5_prime_UTR	Exon 2 of 21	NP_001425575.1
	ATP2B2	NM_001353564.1		c.-3A>G		5_prime_UTR	Exon 3 of 21	NP_001340493.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B2	ENST00000480680.2	TSL:1	n.437A>G		non_coding_transcript_exon	Exon 2 of 6
	ATP2B2	ENST00000360273.7	TSL:5 MANE Select	c.-3A>G		5_prime_UTR	Exon 2 of 23	ENSP00000353414.2
	ATP2B2	ENST00000397077.6	TSL:1	c.-3A>G		5_prime_UTR	Exon 2 of 20	ENSP00000380267.1

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8380 AN: 152220 Hom.: 763 Cov.: 33

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0153 AC: 3860 AN: 251478 AF XY: 0.0114

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00687 AC: 10039 AN: 1461876 Hom.: 725 Cov.: 31 AF XY: 0.00610 AC XY: 4437 AN XY: 727238

African (AFR) AF: 0.197 AC: 6586 AN: 33470

American (AMR) AF: 0.0136 AC: 610 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 331 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86256

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53420

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5768

European-Non Finnish (NFE) AF: 0.00133 AC: 1474 AN: 1112008

Other (OTH) AF: 0.0146 AC: 882 AN: 60396

GnomAD4 genome AF: 0.0551 AC: 8399 AN: 152338 Hom.: 768 Cov.: 33 AF XY: 0.0534 AC XY: 3976 AN XY: 74500

African (AFR) AF: 0.186 AC: 7711 AN: 41562

American (AMR) AF: 0.0276 AC: 422 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00175 AC: 119 AN: 68032

Other (OTH) AF: 0.0402 AC: 85 AN: 2114

Alfa AF: 0.0307 Hom.: 253

Bravo AF: 0.0629

Asia WGS AF: 0.00924 AC: 33 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 23, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.5
DANN	Benign	0.82
PhyloP100		0.10
PromoterAI		-0.0072	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9826066; hg19: chr3-10491230;