12-123724805-C-T

Variant names:

• chr12-123724805-C-T
• rs11837144
• NM_012463.4:c.432+14C>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.432+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,606,302 control chromosomes in the GnomAD database, including 330,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33684 hom., cov: 32)
  • Exomes 𝑓: 0.63 (296376 hom.)
• Consequence: ATP6V0A2 NM_012463.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.72

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=-0.94).
• BP6: Variant 12-123724805-C-T is Benign according to our data. Variant chr12-123724805-C-T is described in ClinVar as [Benign]. Clinvar id is 95524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123724805-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4	c.432+14C>T		intron_variant	Intron 4 of 19	ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2	c.432+14C>T		intron_variant	Intron 4 of 18		XP_024304678.1
ATP6V0A2	XM_024448911.2	c.8+14C>T		intron_variant	Intron 1 of 15		XP_024304679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.432+14C>T		intron_variant	Intron 4 of 19	1	NM_012463.4	ENSP00000332247.2

Frequencies

GnomAD3 genomes AF: 0.664 AC: 100461 AN: 151382 Hom.: 33640 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.668

GnomAD3 exomes AF: 0.682 AC: 171421 AN: 251178 Hom.: 59750 AF XY: 0.674 AC XY: 91448 AN XY: 135766

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.799

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.947

Gnomad SAS exome AF: 0.664

Gnomad FIN exome AF: 0.671

Gnomad NFE exome AF: 0.614

Gnomad OTH exome AF: 0.657

GnomAD4 exome AF: 0.634 AC: 921917 AN: 1454802 Hom.: 296376 Cov.: 33 AF XY: 0.634 AC XY: 458970 AN XY: 724000

Gnomad4 AFR exome AF: 0.675

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.654

Gnomad4 EAS exome AF: 0.955

Gnomad4 SAS exome AF: 0.659

Gnomad4 FIN exome AF: 0.675

Gnomad4 NFE exome AF: 0.609

Gnomad4 OTH exome AF: 0.655

GnomAD4 genome AF: 0.664 AC: 100563 AN: 151500 Hom.: 33684 Cov.: 32 AF XY: 0.668 AC XY: 49447 AN XY: 73988

Gnomad4 AFR AF: 0.678

Gnomad4 AMR AF: 0.742

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.948

Gnomad4 SAS AF: 0.681

Gnomad4 FIN AF: 0.676

Gnomad4 NFE AF: 0.615

Gnomad4 OTH AF: 0.673

Alfa AF: 0.631 Hom.: 45965

Bravo AF: 0.673

Asia WGS AF: 0.817 AC: 2839 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cutis laxa with osteodystrophy Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Wrinkly skin syndrome Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ALG9 congenital disorder of glycosylation Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.030
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs11837144; hg19: chr12-124209352;