X-153556438-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001001344.3(ATP2B3):​c.2326+20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000931 in 1,074,362 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: ATP2B3 NM_001001344.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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>G		intron	N/A	NP_001001344.1
	ATP2B3	NM_001388362.1		c.2326+20C>G		intron	N/A	NP_001375291.1
	ATP2B3	NM_001388361.1		c.2326+20C>G		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>G		intron	N/A	ENSP00000263519.4
	ATP2B3	ENST00000359149.9	TSL:1	c.2326+20C>G		intron	N/A	ENSP00000352062.3
	ATP2B3	ENST00000496610.2	TSL:3	c.2326+20C>G		intron	N/A	ENSP00000516173.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.31e-7 AC: 1 AN: 1074362 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 347208

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26124

American (AMR) AF: 0.00 AC: 0 AN: 31222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18843

East Asian (EAS) AF: 0.0000340 AC: 1 AN: 29452

South Asian (SAS) AF: 0.00 AC: 0 AN: 51336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3472

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 829858

Other (OTH) AF: 0.00 AC: 0 AN: 45179

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.60
DANN	Benign	0.56
PhyloP100		-1.1

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;