2-70964785-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001692.4(ATP6V1B1):āc.1298T>Cā(p.Val433Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V433D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001692.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP6V1B1 | NM_001692.4 | c.1298T>C | p.Val433Ala | missense_variant | 13/14 | ENST00000234396.10 | |
ATP6V1B1 | XM_011532907.3 | c.1418T>C | p.Val473Ala | missense_variant | 12/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP6V1B1 | ENST00000234396.10 | c.1298T>C | p.Val433Ala | missense_variant | 13/14 | 1 | NM_001692.4 | P1 | |
ATP6V1B1 | ENST00000412314.5 | c.1247T>C | p.Val416Ala | missense_variant | 13/14 | 5 | |||
ATP6V1B1 | ENST00000433895.2 | c.230T>C | p.Val77Ala | missense_variant | 4/5 | 3 | |||
VAX2 | ENST00000432367.6 | c.*1074T>C | 3_prime_UTR_variant, NMD_transcript_variant | 14/15 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152022Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251294Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135876
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461764Hom.: 0 Cov.: 33 AF XY: 0.0000591 AC XY: 43AN XY: 727178
GnomAD4 genome AF: 0.000125 AC: 19AN: 152140Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 26, 2022 | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 433 of the ATP6V1B1 protein (p.Val433Ala). This variant is present in population databases (rs149910460, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ATP6V1B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 44224). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Renal tubular acidosis with progressive nerve deafness Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 24, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 20, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Val433Ala varia nt in ATP6V1B1 has not been reported in the literature nor previously identified by our laboratory. Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein. This variant has been identified in 0.04% (2 /4406) of African American chromosomes in a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs149910460). Altho ugh this variant has been seen in the general population, its frequency is not h igh enough to rule out a pathogenic role. In summary, the clinical significance of this variant cannot be determined with certainty; however, based upon observa tion in the general population and no available data to support a disease-causin g role, we would lean towards a more likely benign role. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at