12-123735508-T-C

Variant names:

• chr12-123735508-T-C
• rs2271660
• NM_012463.4:c.732-23T>C

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.732-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,601,846 control chromosomes in the GnomAD database, including 303,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27895 hom., cov: 30)
  • Exomes 𝑓: 0.61 (275557 hom.)
• Consequence: ATP6V0A2 NM_012463.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.16
• 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=-0.92).
• BP6: Variant 12-123735508-T-C is Benign according to our data. Variant chr12-123735508-T-C is described in ClinVar as Benign. ClinVar VariationId is 260260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.924 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.732-23T>C		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.732-23T>C		intron	N/A	ENSP00000332247.2
	ATP6V0A2	ENST00000613625.5	TSL:1	c.732-23T>C		intron	N/A	ENSP00000482236.1
	ATP6V0A2	ENST00000540368.6	TSL:1	n.763-23T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90892 AN: 151700 Hom.: 27861 Cov.: 30

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.618

GnomAD2 exomes AF: 0.651 AC: 163182 AN: 250812 AF XY: 0.643

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.780

Gnomad ASJ exome AF: 0.622

Gnomad EAS exome AF: 0.946

Gnomad FIN exome AF: 0.632

Gnomad NFE exome AF: 0.598

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.612 AC: 887091 AN: 1450028 Hom.: 275557 Cov.: 28 AF XY: 0.612 AC XY: 441669 AN XY: 722086

African (AFR) AF: 0.493 AC: 16364 AN: 33188

American (AMR) AF: 0.773 AC: 34510 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 16214 AN: 26048

East Asian (EAS) AF: 0.954 AC: 37797 AN: 39630

South Asian (SAS) AF: 0.619 AC: 53236 AN: 85934

European-Finnish (FIN) AF: 0.636 AC: 33843 AN: 53236

Middle Eastern (MID) AF: 0.569 AC: 3231 AN: 5676

European-Non Finnish (NFE) AF: 0.594 AC: 654487 AN: 1101664

Other (OTH) AF: 0.624 AC: 37409 AN: 59988

GnomAD4 genome AF: 0.599 AC: 90974 AN: 151818 Hom.: 27895 Cov.: 30 AF XY: 0.605 AC XY: 44894 AN XY: 74202

African (AFR) AF: 0.501 AC: 20702 AN: 41348

American (AMR) AF: 0.705 AC: 10757 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 2151 AN: 3470

East Asian (EAS) AF: 0.946 AC: 4874 AN: 5152

South Asian (SAS) AF: 0.651 AC: 3129 AN: 4808

European-Finnish (FIN) AF: 0.639 AC: 6747 AN: 10564

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40668 AN: 67900

Other (OTH) AF: 0.623 AC: 1311 AN: 2106

Alfa AF: 0.603 Hom.: 75971

Bravo AF: 0.606

Asia WGS AF: 0.789 AC: 2741 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cutis laxa with osteodystrophy (1)
-	-	1	not specified (1)
-	-	1	Wrinkly skin syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.28
DANN	Benign	0.18
PhyloP100		-1.2
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: rs2271660; hg19: chr12-124220055;