rs11681642
Positions:
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1
The NM_001692.4(ATP6V1B1):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 1,612,178 control chromosomes in the GnomAD database, including 148,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.41 ( 12699 hom., cov: 32)
Exomes š: 0.43 ( 135855 hom. )
Consequence
ATP6V1B1
NM_001692.4 start_lost
NM_001692.4 start_lost
Scores
2
4
9
Clinical Significance
Conservation
PhyloP100: 1.64
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
BP6
?
Variant 2-70935956-T-C is Benign according to our data. Variant chr2-70935956-T-C is described in ClinVar as [Benign]. Clinvar id is 44228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-70935956-T-C is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP6V1B1 | NM_001692.4 | c.2T>C | p.Met1? | start_lost | 1/14 | ENST00000234396.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP6V1B1 | ENST00000234396.10 | c.2T>C | p.Met1? | start_lost | 1/14 | 1 | NM_001692.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.406 AC: 61728AN: 151874Hom.: 12693 Cov.: 32
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GnomAD3 exomes AF: 0.400 AC: 99661AN: 249098Hom.: 20838 AF XY: 0.404 AC XY: 54456AN XY: 134780
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GnomAD4 exome AF: 0.429 AC: 625783AN: 1460186Hom.: 135855 Cov.: 36 AF XY: 0.427 AC XY: 310307AN XY: 726338
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GnomAD4 genome ? AF: 0.406 AC: 61755AN: 151992Hom.: 12699 Cov.: 32 AF XY: 0.409 AC XY: 30354AN XY: 74272
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 17, 2021 | Variant summary: ATP6V1B1 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The variant allele was found at a frequency of 0.4 in 249098 control chromosomes in the gnomAD database, including 20838 homozygotes. The observed variant frequency is approximately 357 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP6V1B1 causing Renal Tubular Acidosis With Progressive Nerve Deafness phenotype (0.0011), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 29, 2012 | - - |
Renal tubular acidosis with progressive nerve deafness Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 10, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
P;P
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;.;D
Polyphen
P;.;P
Vest4
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at