X-40606113-A-G

Variant names:

• chrX-40606113-A-G
• rs6609080
• ENST00000636639.1:n.*864A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000636639.1(ATP6AP2):​n.*864A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 196,742 control chromosomes in the GnomAD database, including 412 homozygotes. There are 2,214 hemizygotes in GnomAD. 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 0.049 (291 hom., 1662 hem., cov: 23)
  • Exomes 𝑓: 0.025 (121 hom. 552 hem.)
• Consequence: ATP6AP2 ENST00000636639.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.60
• Publications: 9 publications found

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]

ATP6AP2 Gene-Disease associations (from GenCC):

• ATP6AP2-related disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• congenital disorder of glycosylation, type IIr

  Inheritance: AR, XL Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• syndromic X-linked intellectual disability Hedera type

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked parkinsonism-spasticity syndrome

  Inheritance: XL, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP2	NM_005765.3	c.*358A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000636580.2	NP_005756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP2	ENST00000636580.2	c.*358A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_005765.3	ENSP00000490083.1

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 5548 AN: 112394 Hom.: 290 Cov.: 23

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.00339

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.00864

Gnomad FIN AF: 0.00195

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.00161

Gnomad OTH AF: 0.0549

GnomAD4 exome AF: 0.0250 AC: 2106 AN: 84293 Hom.: 121 Cov.: 0 AF XY: 0.0278 AC XY: 552 AN XY: 19875

African (AFR) AF: 0.104 AC: 281 AN: 2691

American (AMR) AF: 0.208 AC: 731 AN: 3520

Ashkenazi Jewish (ASJ) AF: 0.00217 AC: 5 AN: 2308

East Asian (EAS) AF: 0.196 AC: 790 AN: 4021

South Asian (SAS) AF: 0.00914 AC: 73 AN: 7987

European-Finnish (FIN) AF: 0.00295 AC: 13 AN: 4402

Middle Eastern (MID) AF: 0.00332 AC: 1 AN: 301

European-Non Finnish (NFE) AF: 0.00142 AC: 77 AN: 54236

Other (OTH) AF: 0.0280 AC: 135 AN: 4827

GnomAD4 genome AF: 0.0494 AC: 5554 AN: 112449 Hom.: 291 Cov.: 23 AF XY: 0.0480 AC XY: 1662 AN XY: 34611

African (AFR) AF: 0.102 AC: 3152 AN: 30981

American (AMR) AF: 0.152 AC: 1607 AN: 10558

Ashkenazi Jewish (ASJ) AF: 0.00339 AC: 9 AN: 2655

East Asian (EAS) AF: 0.161 AC: 579 AN: 3606

South Asian (SAS) AF: 0.00830 AC: 23 AN: 2770

European-Finnish (FIN) AF: 0.00195 AC: 12 AN: 6142

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.00161 AC: 86 AN: 53304

Other (OTH) AF: 0.0542 AC: 83 AN: 1530

Alfa AF: 0.0363 Hom.: 1119

Bravo AF: 0.0682

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.59
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs6609080; hg19: chrX-40465365; COSMIC: COSV65798465; COSMIC: COSV65798465;