chr10-16937678-G-T

Position:

chr10-16937678-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001081.4(CUBN):c.5840C>A(p.Ser1947Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00039 in 1,614,036 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 7.06

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUBN	NM_001081.4 linkuse as main transcript	c.5840C>A	p.Ser1947Tyr	missense_variant	39/67	ENST00000377833.10	NP_001072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 linkuse as main transcript	c.5840C>A	p.Ser1947Tyr	missense_variant	39/67	1	NM_001081.4	ENSP00000367064	P1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000263

AC:

AN:

251004

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000407

AC:

595

AN:

1461794

Hom.:

Cov.:

AF XY:

0.000385

AC XY:

280

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000483

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000223

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000318

Hom.:

Bravo

AF:

0.000344

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000296

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CUBN: PM2, PM3 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2023	- -

Proteinuria, chronic benign

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Molecular Biology Laboratory, Fundació Puigvert

Feb 01, 2020

- -

Imerslund-Grasbeck syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

CUBN-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2023

The CUBN c.5840C>A variant is predicted to result in the amino acid substitution p.Ser1947Tyr. This variant was reported in the homozygous state in an individual with nephrotic range proteinuria (Supp. Table 3, P413 Bullich et al 2018. PubMed ID: 29801666). This variant was reported as a variant of uncertain significance in the compound heterozygous and homozygous state in two additional patients with proteinuria (Domingo-Gallego A et al 2022. PubMed ID: 34610128). This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-16979677-G-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Imerslund-Grasbeck syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2022

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1947 of the CUBN protein (p.Ser1947Tyr). This variant is present in population databases (rs147617753, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Imerslund-GraÃàsbeck Syndrome (PMID: 29801666, 31613795, 33532864). ClinVar contains an entry for this variant (Variation ID: 299454). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

4.2

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.46

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MVP

0.85

MPC

0.50

ClinPred

0.46

GERP RS

5.1

Varity_R

0.87

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over