NM_001001331.4:c.199+6303G>A

Variant names:

• chr3-10443042-C-T
• rs17603886
• NM_001001331.4:c.199+6303G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001001331.4(ATP2B2):​c.199+6303G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 152,302 control chromosomes in the GnomAD database, including 87 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 0.030 (87 hom., cov: 32)
• Consequence: ATP2B2 NM_001001331.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.588
• 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):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal dominant 82

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0301 (4589/152302) while in subpopulation NFE AF = 0.0349 (2371/68022). AF 95% confidence interval is 0.0337. There are 87 homozygotes in GnomAd4. There are 2201 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4589 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001331.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B2	NM_001001331.4	MANE Select	c.199+6303G>A		intron	N/A	NP_001001331.1	Q01814-1
	ATP2B2	NM_001438646.1		c.199+6303G>A		intron	N/A	NP_001425575.1
	ATP2B2	NM_001353564.1		c.199+6303G>A		intron	N/A	NP_001340493.1	Q01814-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B2	ENST00000360273.7	TSL:5 MANE Select	c.199+6303G>A		intron	N/A	ENSP00000353414.2	Q01814-1
	ATP2B2	ENST00000452124.2	TSL:1	c.199+6303G>A		intron	N/A	ENSP00000414854.2	Q01814-8
	ATP2B2	ENST00000397077.6	TSL:1	c.199+6303G>A		intron	N/A	ENSP00000380267.1	Q01814-6

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4588 AN: 152184 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0402

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

GnomAD4 genome AF: 0.0301 AC: 4589 AN: 152302 Hom.: 87 Cov.: 32 AF XY: 0.0295 AC XY: 2201 AN XY: 74484

African (AFR) AF: 0.0256 AC: 1062 AN: 41560

American (AMR) AF: 0.0304 AC: 465 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3468

East Asian (EAS) AF: 0.0152 AC: 79 AN: 5182

South Asian (SAS) AF: 0.0131 AC: 63 AN: 4824

European-Finnish (FIN) AF: 0.0253 AC: 269 AN: 10626

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0349 AC: 2371 AN: 68022

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0335 Hom.: 240

Bravo AF: 0.0307

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.6
DANN	Benign	0.77
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs17603886; hg19: chr3-10484726;