Genetic Variant NM_012463.4:c.426T>G (chr12-123724785-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012463.4(ATP6V0A2):c.426T>G(p.Asn142Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N142S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATP6V0A2
NM_012463.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.07

Publications

0 publications found

Variant links:

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)

ATP6V0A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.426T>G	p.Asn142Lys	missense_variant	Exon 4 of 20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448911.2 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 16		XP_024304679.1
ATP6V0A2	XM_024448910.2 link	c.426T>G	p.Asn142Lys	missense_variant	Exon 4 of 19		XP_024304678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 link	c.426T>G	p.Asn142Lys	missense_variant	Exon 4 of 20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461094

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111422

Other (OTH)

AF:

0.0000166

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.0010

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.21

T;.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.74

T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.1

L;.;.

PhyloP100

-4.1

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.53

N;.;N

REVEL

Benign

0.26

Sift

Benign

0.90

T;.;T

Sift4G

Benign

0.81

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.37

MutPred

0.57

Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);.;

MVP

0.19

MPC

0.21

ClinPred

0.035

GERP RS

-7.5

Varity_R

0.032

gMVP

0.27

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over