rs752158933
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_198334.3(GANAB):βc.152_153delβ(p.Arg51LysfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000248 in 1,612,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 31)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
GANAB
NM_198334.3 frameshift
NM_198334.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.52
Genes affected
GANAB (HGNC:4138): (glucosidase II alpha subunit) This gene encodes the alpha subunit of glucosidase II and a member of the glycosyl hydrolase 31 family of proteins. The heterodimeric enzyme glucosidase II plays a role in protein folding and quality control by cleaving glucose residues from immature glycoproteins in the endoplasmic reticulum. Expression of the encoded protein is elevated in lung tumor tissue and in response to UV irradiation. Mutations in this gene cause autosomal-dominant polycystic kidney and liver disease. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 11-62639457-TTC-T is Pathogenic according to our data. Variant chr11-62639457-TTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-62639457-TTC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GANAB | NM_198334.3 | c.152_153del | p.Arg51LysfsTer21 | frameshift_variant | 3/24 | ENST00000356638.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GANAB | ENST00000356638.8 | c.152_153del | p.Arg51LysfsTer21 | frameshift_variant | 3/24 | 1 | NM_198334.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251414Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135888
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460800Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726748
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152032Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74256
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2022 | For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with autosomal dominant polycystic kidney and liver disease (PMID: 27259053). This variant is present in population databases (rs752158933, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg51Lysfs*21) in the GANAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GANAB are known to be pathogenic (PMID: 27259053). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28375157, 27259053) - |
GANAB-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 24, 2024 | The GANAB c.152_153delGA variant is predicted to result in a frameshift and premature protein termination (p.Arg51Lysfs*21). This variant was reported in two affected siblings and in another unrelated individual with polycystic kidney & liver disease, autosomal dominant (Porath et al. 2016. PubMed ID: 27259053; Besse et al. 2017. PubMed ID: 28375157). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in GANAB are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
POLYCYSTIC KIDNEY DISEASE 3 WITH POLYCYSTIC LIVER DISEASE Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 22, 2018 | - - |
Polycystic kidney disease 3 with or without polycystic liver disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 20, 2021 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at