Genetic Variant ATP2B4:c.-194C>T (chr1-203683012-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001684.5(ATP2B4):c.-194C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,644 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATP2B4
NM_001684.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.477

Publications

12 publications found

Variant links:

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]

ATP2B4 links:

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ACMG classification

Classification was made for transcript

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=-0.83).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ATP2B4	NM_001684.5	MANE Select	c.-194C>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	NP_001675.3
ATP2B4	NM_001684.5	MANE Select	c.-194C>T	5_prime_UTR	Exon 2 of 21	NP_001675.3
ATP2B4	NM_001001396.3		c.-194C>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	NP_001001396.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ATP2B4	ENST00000357681.10	TSL:1 MANE Select	c.-194C>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	ENSP00000350310.5
ATP2B4	ENST00000341360.7	TSL:1	c.-194C>T	5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	ENSP00000340930.2
ATP2B4	ENST00000357681.10	TSL:1 MANE Select	c.-194C>T	5_prime_UTR	Exon 2 of 21	ENSP00000350310.5

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

375952

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

195164

African (AFR)

AF:

0.00

AC:

AN:

10908

American (AMR)

AF:

0.00

AC:

AN:

13940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11338

East Asian (EAS)

AF:

0.00

AC:

AN:

25746

South Asian (SAS)

AF:

0.00

AC:

AN:

28332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

237174

Other (OTH)

AF:

0.00

AC:

AN:

21864

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151644

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74032

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41236

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67872

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

2790

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.7

(source)

DANN

Benign

0.76

PhyloP100

-0.48

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over