NM_001692.4:c.89C>T

Variant names:

• chr2-70936043-C-T
• rs17720303
• NM_001692.4:c.89C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001692.4(ATP6V1B1):​c.89C>T​(p.Thr30Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,698 control chromosomes in the GnomAD database, including 24,255 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2144 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22111 hom.)
• Consequence: ATP6V1B1 NM_001692.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.75
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016556978).
• BP6: Variant 2-70936043-C-T is Benign according to our data. Variant chr2-70936043-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.212 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.89C>T	p.Thr30Ile	missense	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.89C>T	p.Thr30Ile	missense	Exon 1 of 14	ENSP00000234396.4	P15313
	ATP6V1B1	ENST00000872157.1		c.89C>T	p.Thr30Ile	missense	Exon 1 of 14	ENSP00000542216.1
	ATP6V1B1	ENST00000872159.1		c.89C>T	p.Thr30Ile	missense	Exon 1 of 14	ENSP00000542218.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25401 AN: 151982 Hom.: 2147 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.185 AC: 46456 AN: 251060 AF XY: 0.181

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.267

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.217

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.172 AC: 251189 AN: 1461598 Hom.: 22111 Cov.: 44 AF XY: 0.172 AC XY: 124795 AN XY: 727116

African (AFR) AF: 0.132 AC: 4410 AN: 33472

American (AMR) AF: 0.261 AC: 11655 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 5868 AN: 26118

East Asian (EAS) AF: 0.208 AC: 8241 AN: 39690

South Asian (SAS) AF: 0.154 AC: 13249 AN: 86238

European-Finnish (FIN) AF: 0.160 AC: 8519 AN: 53386

Middle Eastern (MID) AF: 0.223 AC: 1284 AN: 5764

European-Non Finnish (NFE) AF: 0.168 AC: 187066 AN: 1111850

Other (OTH) AF: 0.180 AC: 10897 AN: 60382

GnomAD4 genome AF: 0.167 AC: 25419 AN: 152100 Hom.: 2144 Cov.: 32 AF XY: 0.167 AC XY: 12383 AN XY: 74354

African (AFR) AF: 0.133 AC: 5527 AN: 41516

American (AMR) AF: 0.218 AC: 3336 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3468

East Asian (EAS) AF: 0.217 AC: 1120 AN: 5156

South Asian (SAS) AF: 0.160 AC: 772 AN: 4810

European-Finnish (FIN) AF: 0.161 AC: 1711 AN: 10600

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11604 AN: 67946

Other (OTH) AF: 0.187 AC: 395 AN: 2114

Alfa AF: 0.173 Hom.: 6062

Bravo AF: 0.176

TwinsUK AF: 0.162 AC: 599

ALSPAC AF: 0.162 AC: 624

ESP6500AA AF: 0.140 AC: 619

ESP6500EA AF: 0.168 AC: 1443

ExAC AF: 0.180 AC: 21833

Asia WGS AF: 0.183 AC: 637 AN: 3478

EpiCase AF: 0.182

EpiControl AF: 0.179

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Renal tubular acidosis with progressive nerve deafness (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0091
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L
PhyloP100		1.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Benign	0.066	T
Polyphen		0.0	B
Vest4		0.41
MPC		0.33
ClinPred		0.017	T
GERP RS		4.9
PromoterAI		0.014	Neutral
Varity_R		0.18
gMVP		0.36
Mutation Taster		=86/14	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: rs17720303; hg19: chr2-71163173; COSMIC: COSV52265977; COSMIC: COSV52265977;