chr12-123751228-G-A

Variant names:

• chr12-123751228-G-A
• rs7969410
• NM_012463.4:c.2054G>A

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.2054G>A​(p.Arg685Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00128 in 1,614,140 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (7 hom.)
• Consequence: ATP6V0A2 NM_012463.4 missense, splice_region
• Scores: Splicing: ADA: 0.5378
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.13
• Publications: 9 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 (MetaRNN=0.0064335465).
• BP6: Variant 12-123751228-G-A is Benign according to our data. Variant chr12-123751228-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0067 (1020/152276) while in subpopulation AFR AF = 0.0228 (948/41552). AF 95% confidence interval is 0.0216. There are 9 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	NM_012463.4	MANE Select	c.2054G>A	p.Arg685Gln	missense splice_region	Exon 16 of 20	NP_036595.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.2054G>A	p.Arg685Gln	missense splice_region	Exon 16 of 20	ENSP00000332247.2
	ATP6V0A2	ENST00000540368.6	TSL:1	n.2085G>A		splice_region non_coding_transcript_exon	Exon 16 of 18
	ATP6V0A2	ENST00000534943.5	TSL:2	c.-107G>A		splice_region	Exon 1 of 5	ENSP00000443726.1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1023 AN: 152158 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00208 AC: 523 AN: 251494 AF XY: 0.00151

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000721 AC: 1054 AN: 1461864 Hom.: 7 Cov.: 30 AF XY: 0.000613 AC XY: 446 AN XY: 727238

African (AFR) AF: 0.0243 AC: 814 AN: 33480

American (AMR) AF: 0.00228 AC: 102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1112000

Other (OTH) AF: 0.00169 AC: 102 AN: 60392

GnomAD4 genome AF: 0.00670 AC: 1020 AN: 152276 Hom.: 9 Cov.: 32 AF XY: 0.00673 AC XY: 501 AN XY: 74456

African (AFR) AF: 0.0228 AC: 948 AN: 41552

American (AMR) AF: 0.00366 AC: 56 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00257 Hom.: 11

Bravo AF: 0.00790

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00235 AC: 285

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ALG9 congenital disorder of glycosylation (1)
-	-	1	ATP6V0A2-related disorder (1)
-	-	1	Cutis laxa with osteodystrophy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.098
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.47
Sift	Benign	0.35	T
Sift4G	Benign	0.53	T
Polyphen		0.32	B
Vest4		0.51
MVP		0.73
MPC		0.31
ClinPred		0.014	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.59
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.38
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: rs7969410; hg19: chr12-124235775;