X-40606021-A-T

Variant names:

• chrX-40606021-A-T
• rs5963816
• NM_005765.3:c.*266A>T

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.*266A>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.08 in 311,272 control chromosomes in the GnomAD database, including 2,994 homozygotes. There are 6,480 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2070 hom., 4297 hem., cov: 23)
  • Exomes 𝑓: 0.048 (924 hom. 2183 hem.)
• Consequence: ATP6AP2 NM_005765.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.97
• Publications: 2 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 (BayesDel_noAF=-0.78).
• BP6: Variant X-40606021-A-T is Benign according to our data. Variant chrX-40606021-A-T is described in ClinVar as Benign. ClinVar VariationId is 1267961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 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.*266A>T		3_prime_UTR	Exon 9 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.*266A>T		3_prime_UTR	Exon 9 of 9	ENSP00000490083.1
	ATP6AP2	ENST00000636639.1	TSL:1	n.*772A>T		non_coding_transcript_exon	Exon 10 of 10	ENSP00000490382.1
	ATP6AP2	ENST00000636639.1	TSL:1	n.*772A>T		3_prime_UTR	Exon 10 of 10	ENSP00000490382.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 15372 AN: 111296 Hom.: 2070 Cov.: 23

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0174

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.0460

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.0475 AC: 9503 AN: 199924 Hom.: 924 Cov.: 0 AF XY: 0.0444 AC XY: 2183 AN XY: 49130

African (AFR) AF: 0.411 AC: 2796 AN: 6809

American (AMR) AF: 0.241 AC: 1737 AN: 7221

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 125 AN: 6452

East Asian (EAS) AF: 0.219 AC: 3046 AN: 13925

South Asian (SAS) AF: 0.0170 AC: 234 AN: 13792

European-Finnish (FIN) AF: 0.00525 AC: 64 AN: 12197

Middle Eastern (MID) AF: 0.0392 AC: 34 AN: 868

European-Non Finnish (NFE) AF: 0.00515 AC: 649 AN: 126085

Other (OTH) AF: 0.0650 AC: 818 AN: 12575

GnomAD4 genome AF: 0.138 AC: 15393 AN: 111348 Hom.: 2070 Cov.: 23 AF XY: 0.128 AC XY: 4297 AN XY: 33580

African (AFR) AF: 0.401 AC: 12201 AN: 30455

American (AMR) AF: 0.193 AC: 2004 AN: 10400

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 46 AN: 2638

East Asian (EAS) AF: 0.158 AC: 564 AN: 3565

South Asian (SAS) AF: 0.0159 AC: 43 AN: 2699

European-Finnish (FIN) AF: 0.00414 AC: 25 AN: 6040

Middle Eastern (MID) AF: 0.0413 AC: 9 AN: 218

European-Non Finnish (NFE) AF: 0.00576 AC: 306 AN: 53154

Other (OTH) AF: 0.130 AC: 195 AN: 1496

Alfa AF: 0.0828 Hom.: 476

Bravo AF: 0.173

ClinVar

ClinVar submissions as Germline

Significance: 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	14
DANN	Benign	0.62
PhyloP100		4.0
Mutation Taster		=100/0	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: rs5963816; hg19: chrX-40465273;