rs142905621

Variant names:

• chr2-70964973-G-A
• rs142905621
• NM_001692.4:c.1394G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-70964973-G-A
• chr2-70964973-G-C
• chr2-70964973-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The ENST00000234396.10(ATP6V1B1):​c.1394G>A​(p.Arg465His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,912 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (29 hom.)
• Consequence: ATP6V1B1 ENST00000234396.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 10.0
• Publications: 14 publications found

Genes affected

ATP6V1B1 (HGNC:853): (ATPase H+ transporting V1 subunit B1) 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 and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain B subunit isoforms and is found in the kidney. Mutations in this gene cause distal renal tubular acidosis associated with sensorineural deafness. [provided by RefSeq, Jul 2008]

ENSG00000258881 (HGNC:):

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0092583).
• BP6: Variant 2-70964973-G-A is Benign according to our data. Variant chr2-70964973-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178290.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00307 (468/152266) while in subpopulation SAS AF = 0.0168 (81/4832). AF 95% confidence interval is 0.0138. There are 7 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000234396.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	NM_001692.4	MANE Select	c.1394G>A	p.Arg465His	missense	Exon 14 of 14	NP_001683.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	ENST00000234396.10	TSL:1 MANE Select	c.1394G>A	p.Arg465His	missense	Exon 14 of 14	ENSP00000234396.4
	ENSG00000258881	ENST00000606025.5	TSL:5	c.476-22540C>T		intron	N/A	ENSP00000475641.1
	ATP6V1B1	ENST00000412314.5	TSL:5	c.1343G>A	p.Arg448His	missense	Exon 14 of 14	ENSP00000388353.1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152148 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00579

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00301 AC: 757 AN: 251130 AF XY: 0.00373

Gnomad AFR exome AF: 0.00862

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00413

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00151 AC: 2204 AN: 1461646 Hom.: 29 Cov.: 33 AF XY: 0.00194 AC XY: 1412 AN XY: 727126

African (AFR) AF: 0.00765 AC: 256 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00597 AC: 237 AN: 39700

South Asian (SAS) AF: 0.0153 AC: 1324 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000170 AC: 189 AN: 1112006

Other (OTH) AF: 0.00272 AC: 164 AN: 60392

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152266 Hom.: 7 Cov.: 31 AF XY: 0.00320 AC XY: 238 AN XY: 74468

African (AFR) AF: 0.00758 AC: 315 AN: 41546

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5172

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00130 Hom.: 4

Bravo AF: 0.00277

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00344 AC: 418

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Renal tubular acidosis with progressive nerve deafness (6)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		10
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.96
MPC		1.1
ClinPred		0.067	T
GERP RS		3.8
Varity_R		0.74
gMVP		0.76
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs142905621; hg19: chr2-71192103;