12-123712552-C-T

Variant names:

• chr12-123712552-C-T
• rs1139320
• NM_012463.4:c.-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.-14C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,562,770 control chromosomes in the GnomAD database, including 111,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10274 hom., cov: 32)
  • Exomes 𝑓: 0.37 (101260 hom.)
• Consequence: ATP6V0A2 NM_012463.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.43
• 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)

LOC105370042 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-123712552-C-T is Benign according to our data. Variant chr12-123712552-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	NM_012463.4	MANE Select	c.-14C>T		5_prime_UTR	Exon 1 of 20	NP_036595.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.-14C>T		5_prime_UTR	Exon 1 of 20	ENSP00000332247.2
	ATP6V0A2	ENST00000613625.5	TSL:1	c.-14C>T		5_prime_UTR	Exon 1 of 9	ENSP00000482236.1
	ATP6V0A2	ENST00000540368.6	TSL:1	n.18C>T		non_coding_transcript_exon	Exon 1 of 18

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54506 AN: 151840 Hom.: 10267 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.354

GnomAD2 exomes AF: 0.322 AC: 54591 AN: 169792 AF XY: 0.330

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.0587

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.372 AC: 525012 AN: 1410818 Hom.: 101260 Cov.: 31 AF XY: 0.371 AC XY: 259445 AN XY: 699290

African (AFR) AF: 0.423 AC: 13482 AN: 31886

American (AMR) AF: 0.210 AC: 8141 AN: 38848

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8137 AN: 25176

East Asian (EAS) AF: 0.0468 AC: 1719 AN: 36702

South Asian (SAS) AF: 0.337 AC: 27498 AN: 81662

European-Finnish (FIN) AF: 0.304 AC: 12897 AN: 42396

Middle Eastern (MID) AF: 0.372 AC: 1964 AN: 5280

European-Non Finnish (NFE) AF: 0.395 AC: 430310 AN: 1090398

Other (OTH) AF: 0.357 AC: 20864 AN: 58470

GnomAD4 genome AF: 0.359 AC: 54545 AN: 151952 Hom.: 10274 Cov.: 32 AF XY: 0.354 AC XY: 26279 AN XY: 74274

African (AFR) AF: 0.407 AC: 16902 AN: 41484

American (AMR) AF: 0.270 AC: 4123 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1135 AN: 3468

East Asian (EAS) AF: 0.0569 AC: 293 AN: 5150

South Asian (SAS) AF: 0.313 AC: 1511 AN: 4828

European-Finnish (FIN) AF: 0.297 AC: 3133 AN: 10544

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.385 AC: 26132 AN: 67882

Other (OTH) AF: 0.349 AC: 738 AN: 2112

Alfa AF: 0.364 Hom.: 1832

Bravo AF: 0.358

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Cutis laxa with osteodystrophy (1)
-	-	1	Cutis Laxa, Recessive (1)
-	-	1	Joubert syndrome (1)
-	-	1	Meckel-Gruber syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		1.4
PromoterAI		-0.075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=299/1	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: rs1139320; hg19: chr12-124197099;