12-123726235-T-G

Variant names:

• chr12-123726235-T-G
• NM_012463.4:c.471T>G
• ATP6V0A2 p.Ser157Arg

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012463.4(ATP6V0A2):​c.471T>G​(p.Ser157Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S157S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP6V0A2 NM_012463.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.67
• 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: ClinGen, Labcorp Genetics (formerly Invitae)
• wrinkly skin syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• autosomal recessive cutis laxa type 2, classic type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044307947).

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.471T>G	p.Ser157Arg	missense	Exon 5 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.471T>G	p.Ser157Arg	missense	Exon 5 of 20	ENSP00000332247.2	Q9Y487
	ATP6V0A2	ENST00000613625.5	TSL:1	c.471T>G	p.Ser157Arg	missense	Exon 5 of 9	ENSP00000482236.1	Q8TBM3
	ATP6V0A2	ENST00000540368.6	TSL:1	n.502T>G		non_coding_transcript_exon	Exon 5 of 18

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.0050
DANN	Benign	0.81
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.16	N
PhyloP100		-2.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.28
Sift	Benign	0.28	T
Sift4G	Benign	0.35	T
Varity_R		0.12
gMVP		0.23
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-124210782;