12-123712449-C-T

Position:

• chr12-123712449-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012463.4(ATP6V0A2):​c.-117C>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 0.00321 in 582,852 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (13 hom.)
• Consequence: ATP6V0A2 NM_012463.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.60

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-123712449-C-T is Benign according to our data. Variant chr12-123712449-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 307576.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0029 (441/152062) while in subpopulation AMR AF= 0.00412 (63/15276). AF 95% confidence interval is 0.00367. There are 1 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4	c.-117C>T		5_prime_UTR_variant	1/20	ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2	c.-117C>T		5_prime_UTR_variant	1/19		XP_024304678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.-117C>T		5_prime_UTR_variant	1/20	1	NM_012463.4	ENSP00000332247	P1
ATP6V0A2	ENST00000613625.5	c.-117C>T		5_prime_UTR_variant	1/9	1		ENSP00000482236
ATP6V0A2	ENST00000675344.1	c.-117C>T		5_prime_UTR_variant, NMD_transcript_variant	1/21			ENSP00000501953

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 151954 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00549

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00432

GnomAD4 exome AF: 0.00332 AC: 1432 AN: 430790 Hom.: 13 Cov.: 6 AF XY: 0.00336 AC XY: 755 AN XY: 224954

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.00583

Gnomad4 ASJ exome AF: 0.000988

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.00490

Gnomad4 NFE exome AF: 0.00385

Gnomad4 OTH exome AF: 0.00324

GnomAD4 genome AF: 0.00290 AC: 441 AN: 152062 Hom.: 1 Cov.: 33 AF XY: 0.00295 AC XY: 219 AN XY: 74348

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00549

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00291

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cutis laxa with osteodystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.2
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs532360215; hg19: chr12-124196996;