rs2266918

Variant names:

• chr2-70943677-C-T
• rs2266918
• NM_001692.4:c.138C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001692.4(ATP6V1B1):​c.138C>T​(p.Ser46Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,456 control chromosomes in the GnomAD database, including 38,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3182 hom., cov: 32)
  • Exomes 𝑓: 0.20 (35805 hom.)
• Consequence: ATP6V1B1 NM_001692.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.39
• Publications: 17 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]

ATP6V1B1-AS1 (HGNC:51118): (ATP6V1B1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-70943677-C-T is Benign according to our data. Variant chr2-70943677-C-T is described in ClinVar as Benign. ClinVar VariationId is 44225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 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.138C>T	p.Ser46Ser	synonymous	Exon 2 of 14	NP_001683.2
	ATP6V1B1-AS1	NR_110273.1		n.524-1244G>A		intron	N/A
	ATP6V1B1-AS1	NR_110274.1		n.386-1244G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1B1	ENST00000234396.10	TSL:1 MANE Select	c.138C>T	p.Ser46Ser	synonymous	Exon 2 of 14	ENSP00000234396.4	P15313
	ENSG00000258881	ENST00000606025.5	TSL:5	c.476-1244G>A		intron	N/A	ENSP00000475641.1	U3KQ87
	ATP6V1B1	ENST00000872157.1		c.138C>T	p.Ser46Ser	synonymous	Exon 2 of 14	ENSP00000542216.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28653 AN: 151946 Hom.: 3176 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.240 AC: 60156 AN: 250570 AF XY: 0.248

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.553

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.204 AC: 298454 AN: 1461390 Hom.: 35805 Cov.: 34 AF XY: 0.210 AC XY: 152781 AN XY: 726992

African (AFR) AF: 0.118 AC: 3940 AN: 33472

American (AMR) AF: 0.196 AC: 8778 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5798 AN: 26132

East Asian (EAS) AF: 0.540 AC: 21434 AN: 39698

South Asian (SAS) AF: 0.395 AC: 34047 AN: 86240

European-Finnish (FIN) AF: 0.243 AC: 12944 AN: 53196

Middle Eastern (MID) AF: 0.288 AC: 1654 AN: 5744

European-Non Finnish (NFE) AF: 0.177 AC: 196591 AN: 1111834

Other (OTH) AF: 0.220 AC: 13268 AN: 60374

GnomAD4 genome AF: 0.189 AC: 28670 AN: 152066 Hom.: 3182 Cov.: 32 AF XY: 0.196 AC XY: 14557 AN XY: 74344

African (AFR) AF: 0.119 AC: 4918 AN: 41490

American (AMR) AF: 0.177 AC: 2709 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3470

East Asian (EAS) AF: 0.525 AC: 2691 AN: 5130

South Asian (SAS) AF: 0.397 AC: 1914 AN: 4826

European-Finnish (FIN) AF: 0.234 AC: 2480 AN: 10612

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12542 AN: 67944

Other (OTH) AF: 0.186 AC: 393 AN: 2108

Alfa AF: 0.173 Hom.: 3001

Bravo AF: 0.175

Asia WGS AF: 0.419 AC: 1459 AN: 3478

EpiCase AF: 0.184

EpiControl AF: 0.180

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Renal tubular acidosis with progressive nerve deafness (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	3.8
DANN	Benign	0.84
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2266918; hg19: chr2-71170807; COSMIC: COSV52268446; COSMIC: COSV52268446;