chrX-40580946-G-C

Variant names:

• chrX-40580946-G-C
• rs186401295
• ENST00000636639.1:n.-120G>C

Variant summary

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

The ENST00000636409.1(ATP6AP2):​c.-120G>C variant causes a 5 prime UTR 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 ENST00000636409.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.367
• 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 Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• syndromic X-linked intellectual disability Hedera type

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

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

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 670923.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 = 0.0188 (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 the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 XL,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000636409.1. 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.-120G>C		upstream_gene	N/A	NP_005756.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	ENST00000636639.1	TSL:1	n.-120G>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000490382.1	A0A1B0GV60
	ATP6AP2	ENST00000636639.1	TSL:1	n.-120G>C		5_prime_UTR	Exon 1 of 10	ENSP00000490382.1	A0A1B0GV60
	ATP6AP2	ENST00000901375.1		c.-120G>C		5_prime_UTR	Exon 1 of 8	ENSP00000571434.1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2125 AN: 113241 Hom.: 17 Cov.: 25

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

GnomAD2 exomes AF: 0.0146 AC: 1466 AN: 100409 AF XY: 0.0138

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 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

African (AFR) AF: 0.0265 AC: 517 AN: 19517

American (AMR) AF: 0.00763 AC: 209 AN: 27391

Ashkenazi Jewish (ASJ) AF: 0.00975 AC: 164 AN: 16825

East Asian (EAS) AF: 0.000117 AC: 3 AN: 25651

South Asian (SAS) AF: 0.0133 AC: 589 AN: 44289

European-Finnish (FIN) AF: 0.0371 AC: 1114 AN: 30029

Middle Eastern (MID) AF: 0.0393 AC: 136 AN: 3462

European-Non Finnish (NFE) AF: 0.0153 AC: 8868 AN: 581130

Other (OTH) AF: 0.0170 AC: 605 AN: 35605

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

African (AFR) AF: 0.0251 AC: 785 AN: 31294

American (AMR) AF: 0.0120 AC: 130 AN: 10866

Ashkenazi Jewish (ASJ) AF: 0.00789 AC: 21 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.0145 AC: 41 AN: 2828

European-Finnish (FIN) AF: 0.0398 AC: 250 AN: 6285

Middle Eastern (MID) AF: 0.0594 AC: 13 AN: 219

European-Non Finnish (NFE) AF: 0.0155 AC: 828 AN: 53334

Other (OTH) AF: 0.0232 AC: 36 AN: 1549

Alfa AF: 0.00900 Hom.: 62

Bravo AF: 0.0176

ClinVar

ClinVar submissions

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	-0.78
CADD	Benign	4.9
DANN	Benign	0.60
PhyloP100		0.37
PromoterAI		-0.17	Neutral
Mutation Taster		=300/0	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: rs186401295; hg19: chrX-40440198;