chr12-123712449-C-T

Variant names:

• chr12-123712449-C-T
• rs532360215
• NM_012463.4:c.-117C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.60
• Publications: 0 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.-117C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	NP_036595.2
	ATP6V0A2	NM_012463.4	MANE Select	c.-117C>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.-117C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	ENSP00000332247.2	Q9Y487
	ATP6V0A2	ENST00000613625.5	TSL:1	c.-117C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000482236.1	Q8TBM3
	ATP6V0A2	ENST00000330342.8	TSL:1 MANE Select	c.-117C>T		5_prime_UTR	Exon 1 of 20	ENSP00000332247.2	Q9Y487

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

African (AFR) AF: 0.000360 AC: 3 AN: 8332

American (AMR) AF: 0.00583 AC: 44 AN: 7552

Ashkenazi Jewish (ASJ) AF: 0.000988 AC: 10 AN: 10120

East Asian (EAS) AF: 0.00 AC: 0 AN: 21240

South Asian (SAS) AF: 0.000134 AC: 4 AN: 29768

European-Finnish (FIN) AF: 0.00490 AC: 132 AN: 26926

Middle Eastern (MID) AF: 0.000585 AC: 1 AN: 1708

European-Non Finnish (NFE) AF: 0.00385 AC: 1164 AN: 302298

Other (OTH) AF: 0.00324 AC: 74 AN: 22846

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

African (AFR) AF: 0.000795 AC: 33 AN: 41530

American (AMR) AF: 0.00412 AC: 63 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00549 AC: 58 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00406 AC: 276 AN: 67942

Other (OTH) AF: 0.00428 AC: 9 AN: 2104

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00291

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cutis laxa with osteodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.2
DANN	Benign	0.91
PhyloP100		-3.6
PromoterAI		-0.090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	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: rs532360215; hg19: chr12-124196996;