X-40580946-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000636639.1(ATP6AP2):c.-120G>C variant causes a 5 prime UTR, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 897,190 control chromosomes in the GnomAD database, including 100 homozygotes. There are 4,188 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (17 hom., 646 hem., cov: 25)
  • Exomes 𝑓: 0.016 (83 hom. 3542 hem.)
• Consequence: ATP6AP2 ENST00000636639.1 5_prime_UTR, NMD_transcript
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.367

Genes affected

ATP6AP2 (HGNC:18305): (ATPase H+ transporting accessory protein 2) This gene encodes a protein that is associated with adenosine triphosphatases (ATPases). Proton-translocating ATPases have fundamental roles in energy conservation, secondary active transport, acidification of intracellular compartments, and cellular pH homeostasis. There are three classes of ATPases- F, P, and V. The vacuolar (V-type) ATPases have a transmembrane proton-conducting sector and an extramembrane catalytic sector. The encoded protein has been found associated with the transmembrane sector of the V-type ATPases. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-40580946-G-C is Benign according to our data. Variant chrX-40580946-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 670923.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0188 (2127/113291) while in subpopulation AFR AF= 0.0251 (785/31294). AF 95% confidence interval is 0.0236. There are 17 homozygotes in gnomad4. There are 646 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6AP2	NM_005765.3			upstream_gene_variant		ENST00000636580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6AP2	ENST00000636580.2			upstream_gene_variant		1	NM_005765.3	P3

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2125 AN: 113241 Hom.: 17 Cov.: 25 AF XY: 0.0182 AC XY: 645 AN XY: 35391

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.0338

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00789

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0398

Gnomad MID AF: 0.0500

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0235

GnomAD3 exomes AF: 0.0146 AC: 1466 AN: 100409 Hom.: 12 AF XY: 0.0138 AC XY: 501 AN XY: 36295

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.00658

Gnomad ASJ exome AF: 0.00841

Gnomad EAS exome AF: 0.000255

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0156 AC: 12205 AN: 783899 Hom.: 83 Cov.: 13 AF XY: 0.0164 AC XY: 3542 AN XY: 216343

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.00763

Gnomad4 ASJ exome AF: 0.00975

Gnomad4 EAS exome AF: 0.000117

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0371

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0188 AC: 2127 AN: 113291 Hom.: 17 Cov.: 25 AF XY: 0.0182 AC XY: 646 AN XY: 35451

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00789

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0398

Gnomad4 NFE AF: 0.0155

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00900 Hom.: 62

Bravo AF: 0.0176

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	4.9
Dann	Benign	0.60

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: rs186401295; hg19: chrX-40440198;