NM_001001331.4:c.2703+9G>T

Variant names:

• chr3-10345375-C-A
• rs241509
• NM_001001331.4:c.2703+9G>T

Variant summary

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

The NM_001001331.4(ATP2B2):​c.2703+9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,613,588 control chromosomes in the GnomAD database, including 156,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11630 hom., cov: 33)
  • Exomes 𝑓: 0.44 (145252 hom.)
• Consequence: ATP2B2 NM_001001331.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.497
• Publications: 11 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=-0.93).
• BP6: Variant 3-10345375-C-A is Benign according to our data. Variant chr3-10345375-C-A is described in ClinVar as Benign. ClinVar VariationId is 1247918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B2	NM_001001331.4	c.2703+9G>T		intron_variant	Intron 18 of 22	ENST00000360273.7	NP_001001331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2B2	ENST00000360273.7	c.2703+9G>T		intron_variant	Intron 18 of 22	5	NM_001001331.4	ENSP00000353414.2

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55629 AN: 152018 Hom.: 11635 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.390

GnomAD2 exomes AF: 0.451 AC: 112944 AN: 250682 AF XY: 0.455

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.593

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.507

Gnomad FIN exome AF: 0.428

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.438

GnomAD4 exome AF: 0.441 AC: 643989 AN: 1461450 Hom.: 145252 Cov.: 48 AF XY: 0.444 AC XY: 322761 AN XY: 727028

African (AFR) AF: 0.144 AC: 4814 AN: 33476

American (AMR) AF: 0.582 AC: 26004 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9495 AN: 26130

East Asian (EAS) AF: 0.561 AC: 22287 AN: 39694

South Asian (SAS) AF: 0.559 AC: 48238 AN: 86242

European-Finnish (FIN) AF: 0.440 AC: 23488 AN: 53380

Middle Eastern (MID) AF: 0.449 AC: 2588 AN: 5762

European-Non Finnish (NFE) AF: 0.433 AC: 481722 AN: 1111684

Other (OTH) AF: 0.420 AC: 25353 AN: 60376

GnomAD4 genome AF: 0.366 AC: 55633 AN: 152138 Hom.: 11630 Cov.: 33 AF XY: 0.373 AC XY: 27764 AN XY: 74364

African (AFR) AF: 0.152 AC: 6302 AN: 41544

American (AMR) AF: 0.508 AC: 7764 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1251 AN: 3468

East Asian (EAS) AF: 0.517 AC: 2659 AN: 5142

South Asian (SAS) AF: 0.546 AC: 2633 AN: 4826

European-Finnish (FIN) AF: 0.430 AC: 4555 AN: 10596

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 29045 AN: 67950

Other (OTH) AF: 0.386 AC: 817 AN: 2114

Alfa AF: 0.392 Hom.: 6991

Bravo AF: 0.358

EpiCase AF: 0.423

EpiControl AF: 0.420

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.4
DANN	Benign	0.78
PhyloP100		-0.50
Mutation Taster		=100/0	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: rs241509; hg19: chr3-10387059; COSMIC: COSV59497093;