chr1-203683389-C-T

Variant names:

• chr1-203683389-C-T
• rs377401279
• NM_001684.5:c.184C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001684.5(ATP2B4):​c.184C>T​(p.Pro62Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATP2B4 NM_001684.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97
• Publications: 1 publications found

Genes affected

ATP2B4 (HGNC:817): (ATPase plasma membrane Ca2+ transporting 4) 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 4. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38570145).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001684.5. 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
	ATP2B4	NM_001684.5	MANE Select	c.184C>T	p.Pro62Ser	missense	Exon 2 of 21	NP_001675.3
	ATP2B4	NM_001001396.3		c.184C>T	p.Pro62Ser	missense	Exon 2 of 22	NP_001001396.1	P23634-2
	ATP2B4	NM_001365783.2		c.184C>T	p.Pro62Ser	missense	Exon 2 of 21	NP_001352712.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B4	ENST00000357681.10	TSL:1 MANE Select	c.184C>T	p.Pro62Ser	missense	Exon 2 of 21	ENSP00000350310.5	P23634-6
	ATP2B4	ENST00000341360.7	TSL:1	c.184C>T	p.Pro62Ser	missense	Exon 2 of 22	ENSP00000340930.2	P23634-2
	ATP2B4	ENST00000890814.1		c.184C>T	p.Pro62Ser	missense	Exon 2 of 21	ENSP00000560873.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457370 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 724574

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 85562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109236

Other (OTH) AF: 0.00 AC: 0 AN: 60180

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.59
Sift	Benign	0.093	T
Sift4G	Benign	0.51	T
Polyphen		0.20	B
Vest4		0.20
MVP		0.69
MPC		1.3
ClinPred		0.97	D
GERP RS		5.9
gMVP		0.78
Mutation Taster		=38/62	disease causing

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: rs377401279; hg19: chr1-203652517;