rs17853498

Variant names:

• chr2-70935981-T-C
• rs17853498
• NM_001692.4:c.27T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001692.4(ATP6V1B1):​c.27T>C​(p.Pro9Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,628 control chromosomes in the GnomAD database, including 10,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1258 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8939 hom.)
• Consequence: ATP6V1B1 NM_001692.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.64
• Publications: 12 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]

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-70935981-T-C is Benign according to our data. Variant chr2-70935981-T-C is described in ClinVar as Benign. ClinVar VariationId is 44227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 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.27T>C	p.Pro9Pro	synonymous	Exon 1 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.27T>C	p.Pro9Pro	synonymous	Exon 1 of 14	ENSP00000234396.4	P15313
	ATP6V1B1	ENST00000872157.1		c.27T>C	p.Pro9Pro	synonymous	Exon 1 of 14	ENSP00000542216.1
	ATP6V1B1	ENST00000872159.1		c.27T>C	p.Pro9Pro	synonymous	Exon 1 of 14	ENSP00000542218.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18017 AN: 151990 Hom.: 1256 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0904

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.118 AC: 29531 AN: 250604 AF XY: 0.122

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0569

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.247

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0879

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.102 AC: 149113 AN: 1461520 Hom.: 8939 Cov.: 39 AF XY: 0.105 AC XY: 76297 AN XY: 727086

African (AFR) AF: 0.166 AC: 5541 AN: 33470

American (AMR) AF: 0.0587 AC: 2624 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3117 AN: 26118

East Asian (EAS) AF: 0.198 AC: 7860 AN: 39696

South Asian (SAS) AF: 0.201 AC: 17361 AN: 86238

European-Finnish (FIN) AF: 0.106 AC: 5651 AN: 53340

Middle Eastern (MID) AF: 0.122 AC: 705 AN: 5762

European-Non Finnish (NFE) AF: 0.0892 AC: 99178 AN: 1111834

Other (OTH) AF: 0.117 AC: 7076 AN: 60366

GnomAD4 genome AF: 0.119 AC: 18030 AN: 152108 Hom.: 1258 Cov.: 32 AF XY: 0.122 AC XY: 9096 AN XY: 74358

African (AFR) AF: 0.160 AC: 6633 AN: 41480

American (AMR) AF: 0.0780 AC: 1193 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 412 AN: 3468

East Asian (EAS) AF: 0.225 AC: 1160 AN: 5154

South Asian (SAS) AF: 0.199 AC: 957 AN: 4810

European-Finnish (FIN) AF: 0.109 AC: 1151 AN: 10608

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0904 AC: 6146 AN: 67980

Other (OTH) AF: 0.112 AC: 236 AN: 2116

Alfa AF: 0.0800 Hom.: 282

Bravo AF: 0.114

Asia WGS AF: 0.182 AC: 633 AN: 3478

EpiCase AF: 0.0921

EpiControl AF: 0.0899

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-0.86
CADD	Benign	2.7
DANN	Benign	0.64
PhyloP100		-2.6
PromoterAI		0.010	Neutral
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17853498; hg19: chr2-71163111; COSMIC: COSV52265970; COSMIC: COSV52265970;