NM_001001344.3:c.148G>C

Variant names:

• chrX-153536395-G-C
• rs1379952932
• NM_001001344.3:c.148G>C

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.148G>C​(p.Glu50Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,091,461 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E50K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: ATP2B3 NM_001001344.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.756
• Publications: 1 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: Unknown, XL Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.03334987).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B3	NM_001001344.3	MANE Select	c.148G>C	p.Glu50Gln	missense	Exon 3 of 22	NP_001001344.1	Q16720-1
	ATP2B3	NM_001388362.1		c.148G>C	p.Glu50Gln	missense	Exon 3 of 22	NP_001375291.1
	ATP2B3	NM_001388361.1		c.148G>C	p.Glu50Gln	missense	Exon 2 of 21	NP_001375290.1	Q16720-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B3	ENST00000263519.5	TSL:1 MANE Select	c.148G>C	p.Glu50Gln	missense	Exon 3 of 22	ENSP00000263519.4	Q16720-1
	ATP2B3	ENST00000359149.9	TSL:1	c.148G>C	p.Glu50Gln	missense	Exon 3 of 23	ENSP00000352062.3	Q16720-2
	ATP2B3	ENST00000496610.2	TSL:3	c.148G>C	p.Glu50Gln	missense	Exon 3 of 23	ENSP00000516173.1	A0A994J5M1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1091461 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 358619

African (AFR) AF: 0.00 AC: 0 AN: 26353

American (AMR) AF: 0.00 AC: 0 AN: 34442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19149

East Asian (EAS) AF: 0.00 AC: 0 AN: 30013

South Asian (SAS) AF: 0.00 AC: 0 AN: 52622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3632

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839740

Other (OTH) AF: 0.00 AC: 0 AN: 45776

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.11
DEOGEN2	Benign	0.044	T
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-2.5	N
PhyloP100		0.76
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.33		Loss of ubiquitination at K48 (P = 0.0801)
MVP		0.78
MPC		0.57
ClinPred		0.064	T
GERP RS		4.0
Varity_R		0.14
gMVP		0.51
Mutation Taster		=99/1	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: rs1379952932; hg19: chrX-152801853;