8-20197449-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001693.4(ATP6V1B2):c.43C>G(p.Pro15Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,539,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ATP6V1B2 NM_001693.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.714

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04849106).
• BP6: Variant 8-20197449-C-G is Benign according to our data. Variant chr8-20197449-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2594749.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V1B2	NM_001693.4	c.43C>G	p.Pro15Ala	missense_variant	1/14	ENST00000276390.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V1B2	ENST00000276390.7	c.43C>G	p.Pro15Ala	missense_variant	1/14	1	NM_001693.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 19 AN: 164556 Hom.: 0 AF XY: 0.000120 AC XY: 11 AN XY: 91768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.000641

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000416

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000440 AC: 61 AN: 1387190 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 36 AN XY: 688832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000306

Gnomad4 SAS exome AF: 0.000454

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000214

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000274 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000997 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.82	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.23
Sift	Benign	0.098	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.43
MutPred		0.28		Loss of glycosylation at P15 (P = 0.0546);
MVP		0.59
MPC		0.013
ClinPred		0.042	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.051
gMVP		0.48

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: rs376671385; hg19: chr8-20054960;