chrX-40580842-C-T

Variant names:

• chrX-40580842-C-T
• rs140128339
• ENST00000436783.6:c.-111+1095C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000436783.6(ATP6AP2):​c.-111+1095C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 488,501 control chromosomes in the GnomAD database, including 22 homozygotes. There are 427 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 0.0099 (13 hom., 298 hem., cov: 25)
  • Exomes 𝑓: 0.0015 (9 hom. 129 hem.)
• Consequence: ATP6AP2 ENST00000436783.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.332
• Publications: 0 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: XL, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• syndromic X-linked intellectual disability Hedera type

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-40580842-C-T is Benign according to our data. Variant chrX-40580842-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 677652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00987 (1116/113117) while in subpopulation AFR AF = 0.0341 (1062/31184). AF 95% confidence interval is 0.0324. There are 13 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 XL,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000436783.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	NM_005765.3	MANE Select	c.-224C>T		upstream_gene	N/A	NP_005756.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	ENST00000436783.6	TSL:5	c.-111+1095C>T		intron	N/A	ENSP00000403969.2	H7C240
	ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.-224C>T		upstream_gene	N/A	ENSP00000490083.1	O75787-1
	ATP6AP2	ENST00000636639.1	TSL:1	n.-224C>T		upstream_gene	N/A	ENSP00000490382.1	A0A1B0GV60

Frequencies

GnomAD3 genomes AF: 0.00988 AC: 1117 AN: 113064 Hom.: 13 Cov.: 25

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000354

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000112

Gnomad OTH AF: 0.00855

GnomAD4 exome AF: 0.00151 AC: 568 AN: 375384 Hom.: 9 Cov.: 4 AF XY: 0.000996 AC XY: 129 AN XY: 129478

African (AFR) AF: 0.0348 AC: 406 AN: 11651

American (AMR) AF: 0.00307 AC: 78 AN: 25393

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13086

East Asian (EAS) AF: 0.00 AC: 0 AN: 22626

South Asian (SAS) AF: 0.00 AC: 0 AN: 35314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24347

Middle Eastern (MID) AF: 0.00130 AC: 3 AN: 2311

European-Non Finnish (NFE) AF: 0.0000365 AC: 8 AN: 219107

Other (OTH) AF: 0.00339 AC: 73 AN: 21549

GnomAD4 genome AF: 0.00987 AC: 1116 AN: 113117 Hom.: 13 Cov.: 25 AF XY: 0.00845 AC XY: 298 AN XY: 35269

African (AFR) AF: 0.0341 AC: 1062 AN: 31184

American (AMR) AF: 0.00314 AC: 34 AN: 10811

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3602

South Asian (SAS) AF: 0.000356 AC: 1 AN: 2812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000112 AC: 6 AN: 53335

Other (OTH) AF: 0.00844 AC: 13 AN: 1540

Alfa AF: 0.00819 Hom.: 24

Bravo AF: 0.0120

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.6
DANN	Benign	0.91
PhyloP100		0.33
PromoterAI		0.18	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140128339; hg19: chrX-40440094;