rs7969410

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012463.4(ATP6V0A2):​c.2054G>A​(p.Arg685Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00128 in 1,614,140 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 9 hom., cov: 32)
Exomes 𝑓: 0.00072 ( 7 hom. )

Consequence

ATP6V0A2
NM_012463.4 missense, splice_region

Scores

1
3
14
Splicing: ADA: 0.5378
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.13
Variant links:
Genes affected
ATP6V0A2 (HGNC:18481): (ATPase H+ transporting V0 subunit a2) The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome. [provided by RefSeq, Jul 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0064335465).
BP6
Variant 12-123751228-G-A is Benign according to our data. Variant chr12-123751228-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235276.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 = 0.0067 (1020/152276) while in subpopulation AFR AF= 0.0228 (948/41552). AF 95% confidence interval is 0.0216. There are 9 homozygotes in gnomad4. There are 501 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP6V0A2NM_012463.4 linkuse as main transcriptc.2054G>A p.Arg685Gln missense_variant, splice_region_variant 16/20 ENST00000330342.8
ATP6V0A2XM_024448911.2 linkuse as main transcriptc.1541G>A p.Arg514Gln missense_variant, splice_region_variant 12/16
ATP6V0A2XM_024448912.2 linkuse as main transcriptc.1232G>A p.Arg411Gln missense_variant, splice_region_variant 9/13
ATP6V0A2XM_024448910.2 linkuse as main transcriptc.1936-1055G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP6V0A2ENST00000330342.8 linkuse as main transcriptc.2054G>A p.Arg685Gln missense_variant, splice_region_variant 16/201 NM_012463.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00672
AC:
1023
AN:
152158
Hom.:
9
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0230
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00367
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:
0.0000588
Gnomad OTH
AF:
0.00574
GnomAD3 exomes
AF:
0.00208
AC:
523
AN:
251494
Hom.:
5
AF XY:
0.00151
AC XY:
205
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.0268
Gnomad AMR exome
AF:
0.00202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000439
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.000721
AC:
1054
AN:
1461864
Hom.:
7
Cov.:
30
AF XY:
0.000613
AC XY:
446
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0243
Gnomad4 AMR exome
AF:
0.00228
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.00169
GnomAD4 genome
AF:
0.00670
AC:
1020
AN:
152276
Hom.:
9
Cov.:
32
AF XY:
0.00673
AC XY:
501
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.0228
Gnomad4 AMR
AF:
0.00366
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00568
Alfa
AF:
0.00114
Hom.:
2
Bravo
AF:
0.00790
ESP6500AA
AF:
0.0218
AC:
96
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00235
AC:
285
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsApr 20, 2015- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJul 11, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
ATP6V0A2-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 18, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
ALG9 congenital disorder of glycosylation Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024- -
Cutis laxa with osteodystrophy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.16
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
T
Eigen
Benign
0.098
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.77
T
MetaRNN
Benign
0.0064
T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.86
N
REVEL
Uncertain
0.47
Sift
Benign
0.35
T
Sift4G
Benign
0.53
T
Polyphen
0.32
B
Vest4
0.51
MVP
0.73
MPC
0.31
ClinPred
0.014
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.12
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.54
dbscSNV1_RF
Benign
0.38
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7969410; hg19: chr12-124235775; API