rs6488898

Variant names:

• chr12-123719285-G-A
• rs6488898
• NM_012463.4:c.196+584G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012463.4(ATP6V0A2):​c.196+584G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 152,236 control chromosomes in the GnomAD database, including 68,834 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.95 (68834 hom., cov: 32)
• Consequence: ATP6V0A2 NM_012463.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.231
• Publications: 26 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)

ENSG00000286092 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4	c.196+584G>A		intron_variant	Intron 2 of 19	ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2	c.196+584G>A		intron_variant	Intron 2 of 18		XP_024304678.1
LOC105370042	XR_945477.4	n.82-3722C>T		intron_variant	Intron 1 of 2
LOC105370042	XR_945478.4	n.82-3722C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.196+584G>A		intron_variant	Intron 2 of 19	1	NM_012463.4	ENSP00000332247.2

Frequencies

GnomAD3 genomes AF: 0.950 AC: 144513 AN: 152118 Hom.: 68779 Cov.: 32

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.927

Gnomad AMR AF: 0.966

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.970

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.950 AC: 144626 AN: 152236 Hom.: 68834 Cov.: 32 AF XY: 0.948 AC XY: 70534 AN XY: 74416

African (AFR) AF: 0.989 AC: 41084 AN: 41542

American (AMR) AF: 0.966 AC: 14753 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.951 AC: 3299 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5189 AN: 5192

South Asian (SAS) AF: 0.969 AC: 4679 AN: 4828

European-Finnish (FIN) AF: 0.866 AC: 9166 AN: 10586

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.930 AC: 63272 AN: 68030

Other (OTH) AF: 0.971 AC: 2048 AN: 2110

Alfa AF: 0.939 Hom.: 229485

Bravo AF: 0.960

Asia WGS AF: 0.987 AC: 3432 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.64
DANN	Benign	0.50
PhyloP100		-0.23
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: rs6488898; hg19: chr12-124203832;