X-153556438-C-T

Variant names:

• chrX-153556438-C-T
• rs2269414
• NM_001001344.3:c.2326+20C>T

Variant summary

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

The NM_001001344.3(ATP2B3):​c.2326+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0835 in 1,185,148 control chromosomes in the GnomAD database, including 4,718 homozygotes. There are 32,347 hemizygotes in GnomAD. 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 0.15 (1577 hom., 4487 hem., cov: 23)
  • Exomes 𝑓: 0.077 (3141 hom. 27860 hem.)
• Consequence: ATP2B3 NM_001001344.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 3 publications found

Genes affected

ATP2B3 (HGNC:816): (ATPase plasma membrane Ca2+ transporting 3) 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 3. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B3 Gene-Disease associations (from GenCC):

• X-linked progressive cerebellar ataxia

  Inheritance: XL, Unknown Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• X-linked non progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001344.3. 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
	ATP2B3	NM_001001344.3	MANE Select	c.2326+20C>T		intron	N/A	NP_001001344.1
	ATP2B3	NM_001388362.1		c.2326+20C>T		intron	N/A	NP_001375291.1
	ATP2B3	NM_001388361.1		c.2326+20C>T		intron	N/A	NP_001375290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B3	ENST00000263519.5	TSL:1 MANE Select	c.2326+20C>T		intron	N/A	ENSP00000263519.4
	ATP2B3	ENST00000359149.9	TSL:1	c.2326+20C>T		intron	N/A	ENSP00000352062.3
	ATP2B3	ENST00000496610.2	TSL:3	c.2326+20C>T		intron	N/A	ENSP00000516173.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 16382 AN: 110838 Hom.: 1575 Cov.: 23

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.0221

Gnomad AMR AF: 0.0660

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0653

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0683

Gnomad OTH AF: 0.145

GnomAD2 exomes AF: 0.0963 AC: 13763 AN: 142899 AF XY: 0.0959

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.0377

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.0849

Gnomad FIN exome AF: 0.0517

Gnomad NFE exome AF: 0.0680

Gnomad OTH exome AF: 0.0841

GnomAD4 exome AF: 0.0769 AC: 82619 AN: 1074258 Hom.: 3141 Cov.: 32 AF XY: 0.0802 AC XY: 27860 AN XY: 347176

African (AFR) AF: 0.360 AC: 9401 AN: 26111

American (AMR) AF: 0.0400 AC: 1250 AN: 31213

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 3269 AN: 18843

East Asian (EAS) AF: 0.0671 AC: 1977 AN: 29451

South Asian (SAS) AF: 0.141 AC: 7228 AN: 51331

European-Finnish (FIN) AF: 0.0527 AC: 2047 AN: 38869

Middle Eastern (MID) AF: 0.144 AC: 501 AN: 3472

European-Non Finnish (NFE) AF: 0.0635 AC: 52696 AN: 829789

Other (OTH) AF: 0.0941 AC: 4250 AN: 45179

GnomAD4 genome AF: 0.148 AC: 16394 AN: 110890 Hom.: 1577 Cov.: 23 AF XY: 0.135 AC XY: 4487 AN XY: 33168

African (AFR) AF: 0.348 AC: 10507 AN: 30206

American (AMR) AF: 0.0658 AC: 701 AN: 10658

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 451 AN: 2633

East Asian (EAS) AF: 0.0655 AC: 229 AN: 3497

South Asian (SAS) AF: 0.126 AC: 321 AN: 2541

European-Finnish (FIN) AF: 0.0511 AC: 314 AN: 6140

Middle Eastern (MID) AF: 0.144 AC: 31 AN: 216

European-Non Finnish (NFE) AF: 0.0683 AC: 3608 AN: 52803

Other (OTH) AF: 0.143 AC: 217 AN: 1517

Alfa AF: 0.122 Hom.: 1200

Bravo AF: 0.157

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.71
DANN	Benign	0.62
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2269414; hg19: chrX-152821896;