chr12-123724805-C-T

Variant names:

• chr12-123724805-C-T
• rs11837144
• NM_012463.4:c.432+14C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• wrinkly skin syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• autosomal recessive cutis laxa type 2, classic type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet
• autosomal recessive cutis laxa type 2A

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-123724805-C-T is Benign according to our data. Variant chr12-123724805-C-T is described in ClinVar as Benign. ClinVar VariationId is 95524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012463.4. 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
	ATP6V0A2	NM_012463.4	MANE Select	c.432+14C>T		intron	N/A	NP_036595.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.432+14C>T		intron	N/A	ENSP00000332247.2
	ATP6V0A2	ENST00000613625.5	TSL:1	c.432+14C>T		intron	N/A	ENSP00000482236.1
	ATP6V0A2	ENST00000540368.6	TSL:1	n.463+14C>T		intron	N/A

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

GnomAD2 exomes AF: 0.682 AC: 171421 AN: 251178 AF XY: 0.674

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 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

African (AFR) AF: 0.675 AC: 22520 AN: 33348

American (AMR) AF: 0.795 AC: 35535 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 17046 AN: 26046

East Asian (EAS) AF: 0.955 AC: 37849 AN: 39642

South Asian (SAS) AF: 0.659 AC: 56720 AN: 86058

European-Finnish (FIN) AF: 0.675 AC: 35933 AN: 53260

Middle Eastern (MID) AF: 0.634 AC: 3649 AN: 5752

European-Non Finnish (NFE) AF: 0.609 AC: 673273 AN: 1105842

Other (OTH) AF: 0.655 AC: 39392 AN: 60160

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

African (AFR) AF: 0.678 AC: 27997 AN: 41298

American (AMR) AF: 0.742 AC: 11290 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2259 AN: 3456

East Asian (EAS) AF: 0.948 AC: 4893 AN: 5164

South Asian (SAS) AF: 0.681 AC: 3275 AN: 4812

European-Finnish (FIN) AF: 0.676 AC: 7060 AN: 10440

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.615 AC: 41725 AN: 67808

Other (OTH) AF: 0.673 AC: 1415 AN: 2104

Alfa AF: 0.636 Hom.: 110253

Bravo AF: 0.673

Asia WGS AF: 0.817 AC: 2839 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Cutis laxa with osteodystrophy (2)
-	-	1	ALG9 congenital disorder of glycosylation (1)
-	-	1	not provided (1)
-	-	1	Wrinkly skin syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.030
DANN	Benign	0.65
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs11837144; hg19: chr12-124209352;