rs150392503

Variant names:

• chrX-40591254-C-T
• rs150392503
• NM_005765.3:c.189C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_005765.3(ATP6AP2):​c.189C>T​(p.Leu63Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,208,683 control chromosomes in the GnomAD database, including 2 homozygotes. There are 166 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 0.0023 (1 hom., 77 hem., cov: 23)
  • Exomes 𝑓: 0.00030 (1 hom. 89 hem.)
• Consequence: ATP6AP2 NM_005765.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.737
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.084).
• BP6: Variant X-40591254-C-T is Benign according to our data. Variant chrX-40591254-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.737 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 77 XL,Unknown gene

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.189C>T	p.Leu63Leu	synonymous	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.189C>T	p.Leu63Leu	synonymous	Exon 3 of 9	ENSP00000490083.1	O75787-1
	ATP6AP2	ENST00000636639.1	TSL:1	n.189C>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000490382.1	A0A1B0GV60
	ATP6AP2	ENST00000637327.1	TSL:2	c.-40C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	ENSP00000490558.1	B7Z413

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 256 AN: 111923 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000571

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00200

GnomAD2 exomes AF: 0.000638 AC: 117 AN: 183379 AF XY: 0.000501

Gnomad AFR exome AF: 0.00828

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000302 AC: 331 AN: 1096708 Hom.: 1 Cov.: 30 AF XY: 0.000245 AC XY: 89 AN XY: 362984

African (AFR) AF: 0.0107 AC: 281 AN: 26355

American (AMR) AF: 0.000199 AC: 7 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54091

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40520

Middle Eastern (MID) AF: 0.000337 AC: 1 AN: 2968

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 842007

Other (OTH) AF: 0.000652 AC: 30 AN: 45981

GnomAD4 genome AF: 0.00229 AC: 256 AN: 111975 Hom.: 1 Cov.: 23 AF XY: 0.00225 AC XY: 77 AN XY: 34153

African (AFR) AF: 0.00787 AC: 243 AN: 30859

American (AMR) AF: 0.000570 AC: 6 AN: 10519

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53186

Other (OTH) AF: 0.00198 AC: 3 AN: 1517

Alfa AF: 0.00156 Hom.: 12

Bravo AF: 0.00282

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Syndromic X-linked intellectual disability Hedera type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.1
DANN	Benign	0.76
PhyloP100		-0.74
PromoterAI		0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=286/14	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: rs150392503; hg19: chrX-40450506;