chr12-123712552-C-T

Position:

• chr12-123712552-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012463.4(ATP6V0A2):​c.-14C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,562,770 control chromosomes in the GnomAD database, including 111,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10274 hom., cov: 32)
  • Exomes 𝑓: 0.37 (101260 hom.)
• Consequence: ATP6V0A2 NM_012463.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-123712552-C-T is Benign according to our data. Variant chr12-123712552-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123712552-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A2	NM_012463.4	c.-14C>T		5_prime_UTR_variant	1/20	ENST00000330342.8
ATP6V0A2	XM_024448910.2	c.-14C>T		5_prime_UTR_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.-14C>T		5_prime_UTR_variant	1/20	1	NM_012463.4	P1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54506 AN: 151840 Hom.: 10267 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.354

GnomAD3 exomes AF: 0.322 AC: 54591 AN: 169792 Hom.: 9728 AF XY: 0.330 AC XY: 31195 AN XY: 94466

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.0587

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.372 AC: 525012 AN: 1410818 Hom.: 101260 Cov.: 31 AF XY: 0.371 AC XY: 259445 AN XY: 699290

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.0468

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.359 AC: 54545 AN: 151952 Hom.: 10274 Cov.: 32 AF XY: 0.354 AC XY: 26279 AN XY: 74274

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.0569

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.349

Alfa AF: 0.364 Hom.: 1832

Bravo AF: 0.358

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cutis laxa, recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Meckel-Gruber syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial aplasia of the vermis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cutis laxa with osteodystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1139320; hg19: chr12-124197099;