rs143944436

Positions:

chr10-16940152-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001081.4(CUBN):c.5428C>T(p.Arg1810Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,614,030 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

CUBN
NM_001081.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.22

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-16940152-G-A is Pathogenic according to our data. Variant chr10-16940152-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 581662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16940152-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUBN	NM_001081.4 linkuse as main transcript	c.5428C>T	p.Arg1810Ter	stop_gained	37/67	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.5428C>T	p.Arg1810Ter	stop_gained	37/67	1	NM_001081.4	ENSP00000367064	P1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251322

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000228

AC:

334

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

165

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000270

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000151

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000161

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2024	Nonsense 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: 25635822, 31589614, 35064937, 31613795) -

Imerslund-Grasbeck syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2023	This sequence change creates a premature translational stop signal (p.Arg1810*) 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 (rs143944436, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of Imerslund-Gr√§sbeck syndrome (PMID: 31613795). ClinVar contains an entry for this variant (Variation ID: 581662). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	May 09, 2018	- -
Likely pathogenic, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 31, 2022

- -

CUBN-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

The CUBN c.5428C>T variant is predicted to result in premature protein termination (p.Arg1810*). This variant was reported with a second CUBN variant in two patients with kidney disease; however, phase of the variants was not determined (Supp. Table 2 in Bedin et al. 2020. PubMed ID: 31613795). Of note, the c.5428C>T has been reported with the c.6088C>T (p.Arg2030*) variant in two patients in the literature, but segregation analysis was not completed to determine phase (Family 21, Supp Table 2 in Bedin et al. 2020. PubMed ID: 31613795; Case #20, Supp. Table 3 in Lu L et al 2022. PubMed ID: 35064937). At PreventionGenetics, we have observed the c.6088C>T and c.5428C>T variants to occur on the same allele (cis phase) based on parental follow up testing (internal data). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. Nonsense variants in CUBN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Autism spectrum disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

Nonsense 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. In our study, two children diagnosed with severe Autism Spectrum Disorder (ASD) are carriers of this mutation, among the two patients, one also carries another variant known to associate with ASD (SRD5A2 (rs9332964)). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

Vest4

0.78

GERP RS

4.3

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