rs786204775
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001081.4(CUBN):c.6928_6934del(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
Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CUBN
NM_001081.4 frameshift
NM_001081.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.37
Genes affected
CUBN (HGNC:2548): (cubilin) Cubilin (CUBN) acts as a receptor for intrinsic factor-vitamin B12 complexes. The role of receptor is supported by the presence of 27 CUB domains. Cubulin is located within the epithelium of intestine and kidney. Mutations in CUBN may play a role in autosomal recessive megaloblastic anemia. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 10-16918687-ATAACCTC-A is Pathogenic according to our data. Variant chr10-16918687-ATAACCTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 189227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16918687-ATAACCTC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CUBN | NM_001081.4 | c.6928_6934del | p.Glu2310CysfsTer3 | frameshift_variant | 45/67 | ENST00000377833.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CUBN | ENST00000377833.10 | c.6928_6934del | p.Glu2310CysfsTer3 | frameshift_variant | 45/67 | 1 | NM_001081.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152200Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
35
AN:
152200
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251342Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135830
GnomAD3 exomes
AF:
AC:
39
AN:
251342
Hom.:
AF XY:
AC XY:
25
AN XY:
135830
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
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 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
504
AN:
1461654
Hom.:
AF XY:
AC XY:
237
AN XY:
727124
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74362
GnomAD4 genome
?
AF:
AC:
35
AN:
152200
Hom.:
Cov.:
32
AF XY:
AC XY:
16
AN XY:
74362
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Imerslund-Grasbeck syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 15, 2014 | 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
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
CUBN-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | 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
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2021 | 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: 31589614, 31613795, 31980526, 23685560) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at