chr12-123743867-A-G

Variant names:

• chr12-123743867-A-G
• rs79134187
• NM_012463.4:c.1121A>G

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.1121A>G​(p.Lys374Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00594 in 1,614,174 control chromosomes in the GnomAD database, including 238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K374E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (104 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (134 hom.)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.18
• Publications: 5 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=0.010434598).
• BP6: Variant 12-123743867-A-G is Benign according to our data. Variant chr12-123743867-A-G is described in ClinVar as Benign. ClinVar VariationId is 95517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V0A2	NM_012463.4	MANE Select	c.1121A>G	p.Lys374Arg	missense	Exon 10 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.1121A>G	p.Lys374Arg	missense	Exon 10 of 20	ENSP00000332247.2
	ATP6V0A2	ENST00000540368.6	TSL:1	n.1152A>G		non_coding_transcript_exon	Exon 10 of 18
	ATP6V0A2	ENST00000504192.2	TSL:5	c.731A>G	p.Lys244Arg	missense	Exon 7 of 9	ENSP00000443441.1

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3377 AN: 152166 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0551

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0113 AC: 2846 AN: 251486 AF XY: 0.00926

Gnomad AFR exome AF: 0.0593

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00718

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00425 AC: 6212 AN: 1461890 Hom.: 134 Cov.: 32 AF XY: 0.00404 AC XY: 2941 AN XY: 727246

African (AFR) AF: 0.0569 AC: 1906 AN: 33480

American (AMR) AF: 0.0422 AC: 1888 AN: 44724

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

East Asian (EAS) AF: 0.00443 AC: 176 AN: 39698

South Asian (SAS) AF: 0.00481 AC: 415 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.00129 AC: 1437 AN: 1112010

Other (OTH) AF: 0.00609 AC: 368 AN: 60396

GnomAD4 genome AF: 0.0222 AC: 3380 AN: 152284 Hom.: 104 Cov.: 32 AF XY: 0.0232 AC XY: 1730 AN XY: 74460

African (AFR) AF: 0.0555 AC: 2306 AN: 41552

American (AMR) AF: 0.0551 AC: 843 AN: 15292

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

East Asian (EAS) AF: 0.00597 AC: 31 AN: 5192

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00151 AC: 103 AN: 68026

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0119 Hom.: 43

Bravo AF: 0.0267

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0583 AC: 257

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.0101 AC: 1232

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	ALG9 congenital disorder of glycosylation (1)
-	-	1	Cutis laxa with osteodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.41
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.099	B
Vest4		0.37
MPC		0.14
ClinPred		0.031	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.83
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs79134187; hg19: chr12-124228414;