8-20197425-C-T

Variant names:

• chr8-20197425-C-T
• rs749448627
• NM_001693.4:c.19C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001693.4(ATP6V1B2):​c.19C>T​(p.Arg7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000935 in 1,390,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: ATP6V1B2 NM_001693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1B2	NM_001693.4	c.19C>T	p.Arg7Trp	missense_variant	Exon 1 of 14	ENST00000276390.7	NP_001684.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1B2	ENST00000276390.7	c.19C>T	p.Arg7Trp	missense_variant	Exon 1 of 14	1	NM_001693.4	ENSP00000276390.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000295 AC: 5 AN: 169252 Hom.: 0 AF XY: 0.0000106 AC XY: 1 AN XY: 94100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000817

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000935 AC: 13 AN: 1390158 Hom.: 0 Cov.: 31 AF XY: 0.00000869 AC XY: 6 AN XY: 690192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000555

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000123

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19C>T (p.R7W) alteration is located in exon 1 (coding exon 1) of the ATP6V1B2 gene. This alteration results from a C to T substitution at nucleotide position 19, causing the arginine (R) at amino acid position 7 to be replaced by a tryptophan (W). 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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.23	N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.70
MutPred		0.42		Loss of disorder (P = 0);
MVP		0.83
MPC		0.030
ClinPred		0.37	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.68

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: rs749448627; hg19: chr8-20054936;