rs757649673

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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 Likely 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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.37

Publications

4 publications found

Variant links:

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]

CUBN Gene-Disease associations (from GenCC):

Imerslund-Grasbeck syndrome type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
proteinuria, chronic benign
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Imerslund-Grasbeck syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CUBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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/Likely_pathogenic. ClinVar VariationId is 189227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4 link	c.6928_6934delGAGGTTA	p.Glu2310CysfsTer3	frameshift_variant	Exon 45 of 67	ENST00000377833.10	NP_001072.2	O60494

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 link	c.6928_6934delGAGGTTA	p.Glu2310CysfsTer3	frameshift_variant	Exon 45 of 67	1	NM_001081.4	ENSP00000367064.4		O60494

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000155

AC:

AN:

251342

AF XY:

0.000184

show subpopulations

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 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.:

AF XY:

0.000326

AC XY:

237

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33466

American (AMR)

AF:

0.000157

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000433

AC:

481

AN:

1111858

Other (OTH)

AF:

0.000199

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000230

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41452

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000219

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Imerslund-Grasbeck syndrome

Pathogenic:2

Dec 15, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Imerslund-Grasbeck syndrome type 1;C5394384:Proteinuria, chronic benign

Pathogenic:1

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chronic kidney disease

Pathogenic:1

Aug 12, 2021

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Proteinuria

Pathogenic:1

Jan 06, 2022

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=6/194

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over