chr1-203683341-G-A

Position:

• chr1-203683341-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001684.5(ATP2B4):​c.136G>A​(p.Val46Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,614,194 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (19 hom.)
• Consequence: ATP2B4 NM_001684.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.30

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003438145).
• BP6: Variant 1-203683341-G-A is Benign according to our data. Variant chr1-203683341-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1584699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B4	NM_001684.5	c.136G>A	p.Val46Ile	missense_variant	2/21	ENST00000357681.10
ATP2B4	NM_001001396.3	c.136G>A	p.Val46Ile	missense_variant	2/22
ATP2B4	NM_001365783.2	c.136G>A	p.Val46Ile	missense_variant	2/21
ATP2B4	NM_001365784.2	c.136G>A	p.Val46Ile	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B4	ENST00000357681.10	c.136G>A	p.Val46Ile	missense_variant	2/21	1	NM_001684.5	A1
ATP2B4	ENST00000341360.7	c.136G>A	p.Val46Ile	missense_variant	2/22	1		P4
ATP2B4	ENST00000705901.1	c.136G>A	p.Val46Ile	missense_variant	2/21

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152196 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00364

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00342 AC: 861 AN: 251446 Hom.: 5 AF XY: 0.00368 AC XY: 500 AN XY: 135892

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00823

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00542

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.00330

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00339 AC: 4963 AN: 1461880 Hom.: 19 Cov.: 33 AF XY: 0.00355 AC XY: 2582 AN XY: 727240

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00823

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00501

Gnomad4 FIN exome AF: 0.00650

Gnomad4 NFE exome AF: 0.00331

Gnomad4 OTH exome AF: 0.00329

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152314 Hom.: 1 Cov.: 31 AF XY: 0.00298 AC XY: 222 AN XY: 74478

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00914

Gnomad4 NFE AF: 0.00364

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00369 Hom.: 2

Bravo AF: 0.00237

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00321 AC: 390

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00397

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ATP2B4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Uncertain	0.98
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.45	T;T;.
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.70	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.041	D;D;D
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.063
MVP		0.24
MPC		0.35
ClinPred		0.0045	T
GERP RS		0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.16

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: rs61731222; hg19: chr1-203652469;