chrX-40591333-C-G

Variant names:

• chrX-40591333-C-G
• rs9014
• NM_005765.3:c.268C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005765.3(ATP6AP2):​c.268C>G​(p.Pro90Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0637 in 1,209,214 control chromosomes in the GnomAD database, including 2,031 homozygotes. There are 24,408 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (106 hom., 1385 hem., cov: 23)
  • Exomes 𝑓: 0.065 (1925 hom. 23023 hem.)
• Consequence: ATP6AP2 NM_005765.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.393
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012736917).
• BP6: Variant X-40591333-C-G is Benign according to our data. Variant chrX-40591333-C-G is described in ClinVar as Benign. ClinVar VariationId is 95311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005765.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	NM_005765.3	MANE Select	c.268C>G	p.Pro90Ala	missense	Exon 3 of 9	NP_005756.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.268C>G	p.Pro90Ala	missense	Exon 3 of 9	ENSP00000490083.1
	ATP6AP2	ENST00000636639.1	TSL:1	n.268C>G		non_coding_transcript_exon	Exon 3 of 10	ENSP00000490382.1
	ATP6AP2	ENST00000378438.9	TSL:5	c.268C>G	p.Pro90Ala	missense	Exon 3 of 9	ENSP00000367697.5

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 5130 AN: 111833 Hom.: 107 Cov.: 23

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0557

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0699

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0424

Gnomad NFE AF: 0.0706

Gnomad OTH AF: 0.0698

GnomAD2 exomes AF: 0.0436 AC: 7988 AN: 183309 AF XY: 0.0434

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0377

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0678

Gnomad OTH exome AF: 0.0583

GnomAD4 exome AF: 0.0655 AC: 71851 AN: 1097325 Hom.: 1925 Cov.: 30 AF XY: 0.0634 AC XY: 23023 AN XY: 362895

African (AFR) AF: 0.00967 AC: 255 AN: 26376

American (AMR) AF: 0.0398 AC: 1400 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 1357 AN: 19378

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30198

South Asian (SAS) AF: 0.0141 AC: 761 AN: 54121

European-Finnish (FIN) AF: 0.0168 AC: 679 AN: 40530

Middle Eastern (MID) AF: 0.0245 AC: 94 AN: 3831

European-Non Finnish (NFE) AF: 0.0768 AC: 64598 AN: 841649

Other (OTH) AF: 0.0587 AC: 2705 AN: 46046

GnomAD4 genome AF: 0.0458 AC: 5125 AN: 111889 Hom.: 106 Cov.: 23 AF XY: 0.0406 AC XY: 1385 AN XY: 34113

African (AFR) AF: 0.0105 AC: 324 AN: 30866

American (AMR) AF: 0.0559 AC: 586 AN: 10488

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 185 AN: 2645

East Asian (EAS) AF: 0.000279 AC: 1 AN: 3586

South Asian (SAS) AF: 0.0141 AC: 38 AN: 2687

European-Finnish (FIN) AF: 0.0148 AC: 90 AN: 6069

Middle Eastern (MID) AF: 0.0372 AC: 8 AN: 215

European-Non Finnish (NFE) AF: 0.0706 AC: 3750 AN: 53128

Other (OTH) AF: 0.0689 AC: 105 AN: 1523

Alfa AF: 0.0558 Hom.: 1220

Bravo AF: 0.0491

TwinsUK AF: 0.0874 AC: 324

ALSPAC AF: 0.0810 AC: 234

ESP6500AA AF: 0.0112 AC: 43

ESP6500EA AF: 0.0719 AC: 484

ExAC AF: 0.0422 AC: 5124

EpiCase AF: 0.0731

EpiControl AF: 0.0744

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Syndromic X-linked intellectual disability Hedera type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.8
DANN	Benign	0.88
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.39
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.11
Sift	Benign	0.78	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.047
MPC		0.51
ClinPred		0.0019	T
GERP RS		-0.75
PromoterAI		-0.00010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.46
Mutation Taster		=96/4	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: rs9014; hg19: chrX-40450585; COSMIC: COSV99058980; COSMIC: COSV99058980;