8-20197423-T-G

Position:

• chr8-20197423-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001693.4(ATP6V1B2):​c.17T>G​(p.Met6Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP6V1B2 NM_001693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

Genes affected

ATP6V1B2 (HGNC:854): (ATPase H+ transporting V1 subunit B2) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. The protein encoded by this gene is one of two V1 domain B subunit isoforms and is the only B isoform highly expressed in osteoclasts. [provided by RefSeq, Jul 2008]

ATP6V1B2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1B2	NM_001693.4	c.17T>G	p.Met6Arg	missense_variant	1/14	ENST00000276390.7	NP_001684.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1B2	ENST00000276390.7	c.17T>G	p.Met6Arg	missense_variant	1/14	1	NM_001693.4	ENSP00000276390.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2024

The c.17T>G (p.M6R) alteration is located in exon 1 (coding exon 1) of the ATP6V1B2 gene. This alteration results from a T to G substitution at nucleotide position 17, causing the methionine (M) at amino acid position 6 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.36	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.18	B
Vest4		0.61
MutPred		0.43		Gain of methylation at M6 (P = 0.0082);
MVP		0.68
MPC		0.014
ClinPred		0.75	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.78

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: rs1270626798; hg19: chr8-20054934;