rs121434430

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001081.4(CUBN):​c.3890C>T​(p.Pro1297Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

9
4
6

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.87
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-17041160-G-A is Pathogenic according to our data. Variant chr10-17041160-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-17041160-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.33633563). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CUBNNM_001081.4 linkc.3890C>T p.Pro1297Leu missense_variant Exon 27 of 67 ENST00000377833.10 NP_001072.2 O60494
CUBNXM_011519708.3 linkc.3890C>T p.Pro1297Leu missense_variant Exon 27 of 55 XP_011518010.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CUBNENST00000377833.10 linkc.3890C>T p.Pro1297Leu missense_variant Exon 27 of 67 1 NM_001081.4 ENSP00000367064.4 O60494

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
151964
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00303
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000330
AC:
83
AN:
251280
Hom.:
0
AF XY:
0.000324
AC XY:
44
AN XY:
135810
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00346
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000153
AC:
224
AN:
1461440
Hom.:
0
Cov.:
31
AF XY:
0.000144
AC XY:
105
AN XY:
727036
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00320
Gnomad4 NFE exome
AF:
0.0000396
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
151964
Hom.:
0
Cov.:
32
AF XY:
0.000350
AC XY:
26
AN XY:
74196
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00303
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000567
Hom.:
0
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000305
AC:
37
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Imerslund-Grasbeck syndrome Pathogenic:2
Feb 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1297 of the CUBN protein (p.Pro1297Leu). This variant is present in population databases (rs121434430, gnomAD 0.3%). This missense change has been observed in individuals with megaloblastic anemia 1 (PMID: 7573042, 10080186). It is commonly reported in individuals of Finn ancestry (PMID: 7573042, 10080186). ClinVar contains an entry for this variant (Variation ID: 6689). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CUBN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CUBN function (PMID: 10887099, 24156255). For these reasons, this variant has been classified as Pathogenic. -

-
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Imerslund-Grasbeck syndrome type 1;C5394384:Proteinuria, chronic benign Pathogenic:1
Mar 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Imerslund-Grasbeck syndrome type 1 Pathogenic:1
Jul 15, 2000
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
T
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.34
T
MetaSVM
Uncertain
0.096
D
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-9.7
D
REVEL
Uncertain
0.64
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MVP
0.91
MPC
0.45
ClinPred
0.68
D
GERP RS
5.8
Varity_R
0.87
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121434430; hg19: chr10-17083159; COSMIC: COSV64729702; API