NM_001081.4:c.6928_6934delGAGGTTA
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001081.4(CUBN):c.6928_6934delGAGGTTA(p.Glu2310CysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001081.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000230 AC: 35AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251342Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135830
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000345 AC: 504AN: 1461654Hom.: 0 AF XY: 0.000326 AC XY: 237AN XY: 727124
GnomAD4 genome AF: 0.000230 AC: 35AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74362
ClinVar
Submissions by phenotype
Imerslund-Grasbeck syndrome Pathogenic:2
This sequence change creates a premature translational stop signal (p.Glu2310Cysfs*3) in the CUBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CUBN are known to be pathogenic (PMID: 15024727, 22929189, 25349199, 31613795, 34979989). This variant is present in population databases (rs757649673, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 189227). For these reasons, this variant has been classified as Pathogenic. -
The Glu2310CysfsX3 variant is predicted to alter the protein’s amino acid sequence beginning at position 2310 and lead to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria for pathogenicity. -
Imerslund-Grasbeck syndrome type 1;C5394384:Proteinuria, chronic benign Pathogenic:1
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Chronic kidney disease Pathogenic:1
This variant (c.6928_6934del, p.Glu2310Cysfs*3) predicts a frameshift to a premature stop codon. It has been observed at extremely low frequency in population databases (gnomAD) and has been reported in the literature (PMID 25349199, 22929189, 15024727), although no functional studies have been reported. The change was identified as homozygous in an affected patient. -
CUBN-related disorder Pathogenic:1
The CUBN c.6928_6934del7 variant is predicted to result in a frameshift and premature protein termination (p.Glu2310Cysfs*3). This variant has been reported along with a second truncating variant in a patient with chronic proteinuria (Table S2 of Bedin et al. 2020. PubMed ID: 31613795). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CUBN are expected to be pathogenic. This variant is interpreted as pathogenic. -
not provided Pathogenic:1
Identified with a second CUBN variant in a patient with persistent nephrotic proteinuria, diffuse foot process effacement of podocytes, and variable thickness of the glomerular basal membrane in published literature (PMID: 36913226); 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; This variant is associated with the following publications: (PMID: 23685560, 31980526, 31589614, 36913226, 31613795) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at