rs12259370

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001081.4(CUBN):c.196G>A(p.Gly66Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00447 in 1,613,334 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 105 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 105 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.83

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006356895).

BP6

Variant 10-17129177-C-T is Benign according to our data. Variant chr10-17129177-C-T is described in ClinVar as [Benign]. Clinvar id is 299546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-17129177-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4 link	c.196G>A	p.Gly66Arg	missense_variant	Exon 2 of 67	ENST00000377833.10	NP_001072.2	O60494
CUBN	XM_011519708.3 link	c.196G>A	p.Gly66Arg	missense_variant	Exon 2 of 55		XP_011518010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 link	c.196G>A	p.Gly66Arg	missense_variant	Exon 2 of 67	1	NM_001081.4	ENSP00000367064.4		O60494
CUBN	ENST00000377823.1 link	n.235G>A		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0208

AC:

3159

AN:

152078

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0701

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00975

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00581

AC:

1460

AN:

251276

Hom.:

AF XY:

0.00434

AC XY:

590

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0690

Gnomad AMR exome

AF:

0.00506

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00277

AC:

4048

AN:

1461138

Hom.:

105

Cov.:

AF XY:

0.00242

AC XY:

1756

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.0731

Gnomad4 AMR exome

AF:

0.00579

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000603

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000787

Gnomad4 OTH exome

AF:

0.00568

GnomAD4 genome

AF:

0.0208

AC:

3166

AN:

152196

Hom.:

105

Cov.:

AF XY:

0.0202

AC XY:

1502

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0701

Gnomad4 AMR

AF:

0.00974

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.00499

Hom.:

Bravo

AF:

0.0234

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0679

AC:

299

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00680

AC:

826

Asia WGS

AF:

0.00433

AC:

AN:

3476

EpiCase

AF:

0.00115

EpiControl

AF:

0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30900415, 26827111) -

Imerslund-Grasbeck syndrome type 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Imerslund-Grasbeck syndrome

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.61

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.63

MutPred

0.69

Gain of MoRF binding (P = 0.0299);

MVP

0.96

MPC

0.49

ClinPred

0.025

GERP RS

5.0

Varity_R

0.50

gMVP

0.61

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