rs786204775

Positions:

• chr10-16918687-ATAACCTC-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

ACMG classification

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: 35 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251342 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135830

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.000489

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000345 AC: 504 AN: 1461654 Hom.: 0 AF XY: 0.000326 AC XY: 237 AN XY: 727124

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000433

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74362

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000219

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757649673; hg19: chr10-16960686;