1-203698281-T-C

Position:

• chr1-203698281-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001684.5(ATP2B4):​c.318T>C​(p.Leu106=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.888 in 1,613,900 control chromosomes in the GnomAD database, including 638,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55042 hom., cov: 30)
  • Exomes 𝑓: 0.89 (583661 hom.)
• Consequence: ATP2B4 NM_001684.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.41

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-203698281-T-C is Benign according to our data. Variant chr1-203698281-T-C is described in ClinVar as [Benign]. Clinvar id is 1600570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B4	NM_001684.5	c.318T>C	p.Leu106=	synonymous_variant	3/21	ENST00000357681.10
ATP2B4	NM_001001396.3	c.318T>C	p.Leu106=	synonymous_variant	3/22
ATP2B4	NM_001365783.2	c.318T>C	p.Leu106=	synonymous_variant	3/21
ATP2B4	NM_001365784.2	c.318T>C	p.Leu106=	synonymous_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B4	ENST00000357681.10	c.318T>C	p.Leu106=	synonymous_variant	3/21	1	NM_001684.5	A1
ATP2B4	ENST00000341360.7	c.318T>C	p.Leu106=	synonymous_variant	3/22	1		P4
ATP2B4	ENST00000705901.1	c.318T>C	p.Leu106=	synonymous_variant	3/21

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128667 AN: 151948 Hom.: 55016 Cov.: 30

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.909

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.890

Gnomad OTH AF: 0.871

GnomAD3 exomes AF: 0.886 AC: 222871 AN: 251416 Hom.: 99295 AF XY: 0.886 AC XY: 120330 AN XY: 135874

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.947

Gnomad ASJ exome AF: 0.900

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.864

Gnomad FIN exome AF: 0.829

Gnomad NFE exome AF: 0.888

Gnomad OTH exome AF: 0.892

GnomAD4 exome AF: 0.893 AC: 1304746 AN: 1461834 Hom.: 583661 Cov.: 62 AF XY: 0.891 AC XY: 648213 AN XY: 727216

Gnomad4 AFR exome AF: 0.717

Gnomad4 AMR exome AF: 0.943

Gnomad4 ASJ exome AF: 0.900

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.858

Gnomad4 FIN exome AF: 0.830

Gnomad4 NFE exome AF: 0.897

Gnomad4 OTH exome AF: 0.893

GnomAD4 genome AF: 0.847 AC: 128740 AN: 152066 Hom.: 55042 Cov.: 30 AF XY: 0.846 AC XY: 62883 AN XY: 74328

Gnomad4 AFR AF: 0.729

Gnomad4 AMR AF: 0.909

Gnomad4 ASJ AF: 0.908

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.854

Gnomad4 FIN AF: 0.823

Gnomad4 NFE AF: 0.890

Gnomad4 OTH AF: 0.872

Alfa AF: 0.872 Hom.: 29229

Bravo AF: 0.851

Asia WGS AF: 0.931 AC: 3238 AN: 3478

EpiCase AF: 0.894

EpiControl AF: 0.889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.4
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228445; hg19: chr1-203667409;