8-20197417-G-A

Position:

• chr8-20197417-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001693.4(ATP6V1B2):​c.11G>A​(p.Arg4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,542,040 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (48 hom.)
• Consequence: ATP6V1B2 NM_001693.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009298593).
• BP6: Variant 8-20197417-G-A is Benign according to our data. Variant chr8-20197417-G-A is described in ClinVar as [Benign]. Clinvar id is 770944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 734 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1B2	NM_001693.4	c.11G>A	p.Arg4Gln	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.11G>A	p.Arg4Gln	missense_variant	1/14	1	NM_001693.4	ENSP00000276390	P1

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 734 AN: 152178 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00737

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00446 AC: 745 AN: 166914 Hom.: 0 AF XY: 0.00462 AC XY: 429 AN XY: 92816

Gnomad AFR exome AF: 0.00267

Gnomad AMR exome AF: 0.00525

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00693

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00631 AC: 8763 AN: 1389744 Hom.: 48 Cov.: 31 AF XY: 0.00632 AC XY: 4359 AN XY: 690218

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00561

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00185

Gnomad4 FIN exome AF: 0.000438

Gnomad4 NFE exome AF: 0.00734

Gnomad4 OTH exome AF: 0.00610

GnomAD4 genome AF: 0.00482 AC: 734 AN: 152296 Hom.: 1 Cov.: 33 AF XY: 0.00454 AC XY: 338 AN XY: 74462

Gnomad4 AFR AF: 0.00216

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00737

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00659 Hom.: 8

Bravo AF: 0.00566

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00251 AC: 11

ESP6500EA AF: 0.00724 AC: 62

ExAC AF: 0.00386 AC: 464

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ATP6V1B2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.049
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.68	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.030	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.013	D
Sift4G	Benign	0.23	T
Polyphen		0.0040	B
Vest4		0.44
MVP		0.83
MPC		0.014
ClinPred		0.061	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.17
gMVP		0.72

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: rs116941637; hg19: chr8-20054928;