12-123735508-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012463.4(ATP6V0A2):​c.732-23T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,603,314 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (10 hom., cov: 30)
  • Exomes 𝑓: 0.0032 (45 hom.)
• Consequence: ATP6V0A2 NM_012463.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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):

• autosomal recessive cutis laxa type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• 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: Genomics England PanelApp, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-123735508-T-G is Benign according to our data. Variant chr12-123735508-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1218895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0046 (699/151922) while in subpopulation NFE AF = 0.00449 (305/67944). AF 95% confidence interval is 0.00407. There are 10 homozygotes in GnomAd4. There are 415 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	NM_012463.4	MANE Select	c.732-23T>G		intron	N/A	NP_036595.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.732-23T>G		intron	N/A	ENSP00000332247.2	Q9Y487
	ATP6V0A2	ENST00000613625.5	TSL:1	c.732-23T>G		intron	N/A	ENSP00000482236.1	Q8TBM3
	ATP6V0A2	ENST00000540368.6	TSL:1	n.763-23T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 699 AN: 151804 Hom.: 10 Cov.: 30

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00449

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00469 AC: 1176 AN: 250812 AF XY: 0.00458

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00325 AC: 4711 AN: 1451392 Hom.: 45 Cov.: 28 AF XY: 0.00331 AC XY: 2394 AN XY: 722704

African (AFR) AF: 0.000211 AC: 7 AN: 33216

American (AMR) AF: 0.000291 AC: 13 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.000844 AC: 22 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85966

European-Finnish (FIN) AF: 0.0331 AC: 1763 AN: 53272

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5686

European-Non Finnish (NFE) AF: 0.00252 AC: 2779 AN: 1102840

Other (OTH) AF: 0.00207 AC: 124 AN: 60042

GnomAD4 genome AF: 0.00460 AC: 699 AN: 151922 Hom.: 10 Cov.: 30 AF XY: 0.00559 AC XY: 415 AN XY: 74246

African (AFR) AF: 0.000169 AC: 7 AN: 41392

American (AMR) AF: 0.000458 AC: 7 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0353 AC: 373 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00449 AC: 305 AN: 67944

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.000377 Hom.: 75971

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.24
DANN	Benign	0.29
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

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;