12-123744882-T-C

Position:

chr12-123744882-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012463.4(ATP6V0A2):c.1515T>C(p.Asn505=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 1,613,844 control chromosomes in the GnomAD database, including 347,608 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 39330 hom., cov: 32)

Exomes 𝑓: 0.65 ( 308278 hom. )

Consequence

ATP6V0A2
NM_012463.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00005240

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.06

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]

ATP6V0A2 links:

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 (BayesDel_noAF=-0.82).

BP6

Variant 12-123744882-T-C is Benign according to our data. Variant chr12-123744882-T-C is described in ClinVar as [Benign]. Clinvar id is 95520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123744882-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATP6V0A2	NM_012463.4 linkuse as main transcript	c.1515T>C	p.Asn505=	splice_region_variant, synonymous_variant	13/20	ENST00000330342.8
ATP6V0A2	XM_024448910.2 linkuse as main transcript	c.1515T>C	p.Asn505=	splice_region_variant, synonymous_variant	13/19
ATP6V0A2	XM_024448911.2 linkuse as main transcript	c.1002T>C	p.Asn334=	splice_region_variant, synonymous_variant	9/16
ATP6V0A2	XM_024448912.2 linkuse as main transcript	c.693T>C	p.Asn231=	splice_region_variant, synonymous_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A2	ENST00000330342.8 linkuse as main transcript	c.1515T>C	p.Asn505=	splice_region_variant, synonymous_variant	13/20	1	NM_012463.4	P1

Frequencies

GnomAD3 genomes

AF:

0.712

AC:

108223

AN:

152036

Hom.:

39267

Cov.:

show subpopulations

Gnomad AFR

AF:

0.830

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.759

Gnomad ASJ

AF:

0.663

Gnomad EAS

AF:

0.950

Gnomad SAS

AF:

0.681

Gnomad FIN

AF:

0.681

Gnomad MID

AF:

0.621

Gnomad NFE

AF:

0.624

Gnomad OTH

AF:

0.700

GnomAD3 exomes

AF:

0.698

AC:

175478

AN:

251466

Hom.:

62614

AF XY:

0.686

AC XY:

93239

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.836

Gnomad AMR exome

AF:

0.808

Gnomad ASJ exome

AF:

0.662

Gnomad EAS exome

AF:

0.949

Gnomad SAS exome

AF:

0.665

Gnomad FIN exome

AF:

0.674

Gnomad NFE exome

AF:

0.622

Gnomad OTH exome

AF:

0.667

GnomAD4 exome

AF:

0.645

AC:

942865

AN:

1461688

Hom.:

308278

Cov.:

AF XY:

0.645

AC XY:

468668

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.828

Gnomad4 AMR exome

AF:

0.804

Gnomad4 ASJ exome

AF:

0.663

Gnomad4 EAS exome

AF:

0.957

Gnomad4 SAS exome

AF:

0.660

Gnomad4 FIN exome

AF:

0.677

Gnomad4 NFE exome

AF:

0.617

Gnomad4 OTH exome

AF:

0.671

GnomAD4 genome

AF:

0.712

AC:

108349

AN:

152156

Hom.:

39330

Cov.:

AF XY:

0.714

AC XY:

53130

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.830

Gnomad4 AMR

AF:

0.759

Gnomad4 ASJ

AF:

0.663

Gnomad4 EAS

AF:

0.950

Gnomad4 SAS

AF:

0.682

Gnomad4 FIN

AF:

0.681

Gnomad4 NFE

AF:

0.624

Gnomad4 OTH

AF:

0.704

Alfa

AF:

0.648

Hom.:

70558

Bravo

AF:

0.726

Asia WGS

AF:

0.831

AC:

2889

AN:

3478

EpiCase

AF:

0.622

EpiControl

AF:

0.623

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2016	This 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2012	- -

Cutis laxa with osteodystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Wrinkly skin syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

ALG9 congenital disorder of glycosylation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.20

DANN

Benign

0.44

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000052

dbscSNV1_RF

Benign

0.018

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 6

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over