rs114234874

Variant names:

• chr2-70959974-G-A
• rs114234874
• NM_001692.4:c.481G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP6 BA1

The NM_001692.4(ATP6V1B1):​c.481G>A​(p.Glu161Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,614,138 control chromosomes in the GnomAD database, including 794 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. E161Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (65 hom., cov: 32)
  • Exomes 𝑓: 0.025 (729 hom.)
• Consequence: ATP6V1B1 NM_001692.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:14
• Conservation: PhyloP100: 9.99
• Publications: 24 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 -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001692.4
• BP6: Variant 2-70959974-G-A is Benign according to our data. Variant chr2-70959974-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44229.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001692.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	NM_001692.4	MANE Select	c.481G>A	p.Glu161Lys	missense	Exon 6 of 14	NP_001683.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	ENST00000234396.10	TSL:1 MANE Select	c.481G>A	p.Glu161Lys	missense	Exon 6 of 14	ENSP00000234396.4	P15313
	ENSG00000258881	ENST00000606025.5	TSL:5	c.476-17541C>T		intron	N/A	ENSP00000475641.1	U3KQ87
	ATP6V1B1	ENST00000872157.1		c.481G>A	p.Glu161Lys	missense	Exon 6 of 14	ENSP00000542216.1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3957 AN: 152156 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0553

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0300 AC: 7535 AN: 251352 AF XY: 0.0334

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0586

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0525

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0249 AC: 36452 AN: 1461864 Hom.: 729 Cov.: 32 AF XY: 0.0269 AC XY: 19550 AN XY: 727238

African (AFR) AF: 0.0274 AC: 919 AN: 33480

American (AMR) AF: 0.0136 AC: 607 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 1539 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0712 AC: 6140 AN: 86258

European-Finnish (FIN) AF: 0.0528 AC: 2820 AN: 53408

Middle Eastern (MID) AF: 0.0690 AC: 398 AN: 5768

European-Non Finnish (NFE) AF: 0.0201 AC: 22306 AN: 1111996

Other (OTH) AF: 0.0284 AC: 1716 AN: 60394

GnomAD4 genome AF: 0.0260 AC: 3960 AN: 152274 Hom.: 65 Cov.: 32 AF XY: 0.0275 AC XY: 2050 AN XY: 74442

African (AFR) AF: 0.0261 AC: 1087 AN: 41568

American (AMR) AF: 0.0184 AC: 281 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 192 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0644 AC: 311 AN: 4828

European-Finnish (FIN) AF: 0.0491 AC: 521 AN: 10602

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1477 AN: 68008

Other (OTH) AF: 0.0331 AC: 70 AN: 2116

Alfa AF: 0.0234 Hom.: 171

Bravo AF: 0.0222

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.0219 AC: 188

ExAC AF: 0.0306 AC: 3714

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.47	N
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.46
MPC		0.35
ClinPred		0.024	T
GERP RS		4.5
Varity_R		0.28
gMVP		0.79
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: 3

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

Other links and lift over

dbSNP: rs114234874; hg19: chr2-71187104;