NM_005765.3:c.268C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005765.3(ATP6AP2):​c.268C>T​(p.Pro90Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,848 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P90A) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: ATP6AP2 NM_005765.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040079206).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	NM_005765.3	MANE Select	c.268C>T	p.Pro90Ser	missense	Exon 3 of 9	NP_005756.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.268C>T	p.Pro90Ser	missense	Exon 3 of 9	ENSP00000490083.1	O75787-1
	ATP6AP2	ENST00000636639.1	TSL:1	n.268C>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000490382.1	A0A1B0GV60
	ATP6AP2	ENST00000901377.1		c.268C>T	p.Pro90Ser	missense	Exon 3 of 9	ENSP00000571436.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111848 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111848 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34050

African (AFR) AF: 0.0000325 AC: 1 AN: 30799

American (AMR) AF: 0.00 AC: 0 AN: 10480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6069

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53140

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.00 Hom.: 1220

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.39
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.049
Sift	Benign	0.48	T
Sift4G	Benign	0.18	T
Polyphen		0.014	B
Vest4		0.080
MutPred		0.23		Loss of catalytic residue at P89 (P = 0.0195)
MVP		0.28
MPC		0.54
ClinPred		0.11	T
GERP RS		-0.75
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.47
Mutation Taster		=93/7	polymorphism

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;