rs146027947

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001081.4(CUBN):c.10039G>A(p.Gly3347Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,613,966 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 31 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.158

Publications

2 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038042367).

BP6

Variant 10-16836376-C-T is Benign according to our data. Variant chr10-16836376-C-T is described in ClinVar as Benign. ClinVar VariationId is 299371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00777 (1183/152286) while in subpopulation EAS AF = 0.0372 (193/5186). AF 95% confidence interval is 0.0329. There are 16 homozygotes in GnomAd4. There are 575 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CUBN	NM_001081.4 link	c.10039G>A	p.Gly3347Arg	missense_variant	Exon 63 of 67	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3 link	c.6025G>A	p.Gly2009Arg	missense_variant	Exon 37 of 41		XP_011518011.1
CUBN	XM_011519710.3 link	c.6001G>A	p.Gly2001Arg	missense_variant	Exon 37 of 41		XP_011518012.1
CUBN	XM_011519711.4 link	c.5881G>A	p.Gly1961Arg	missense_variant	Exon 36 of 40		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 link	c.10039G>A	p.Gly3347Arg	missense_variant	Exon 63 of 67	1	NM_001081.4	ENSP00000367064.4

Frequencies

GnomAD3 genomes

AF:

0.00777

AC:

1182

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0216

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0375

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00507

AC:

1272

AN:

250972

AF XY:

0.00424

show subpopulations

Gnomad AFR exome

AF:

0.0234

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0418

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00171

AC:

2497

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1166

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.0197

AC:

660

AN:

33470

American (AMR)

AF:

0.00132

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.0284

AC:

1126

AN:

39692

South Asian (SAS)

AF:

0.00122

AC:

105

AN:

86242

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000252

AC:

280

AN:

1111854

Other (OTH)

AF:

0.00406

AC:

245

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

129

259

388

518

647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00777

AC:

1183

AN:

152286

Hom.:

Cov.:

AF XY:

0.00772

AC XY:

575

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0216

AC:

896

AN:

41554

American (AMR)

AF:

0.00301

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0372

AC:

193

AN:

5186

South Asian (SAS)

AF:

0.00187

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68022

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00209

Hom.:

Bravo

AF:

0.00880

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00521

AC:

633

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1

Benign:1

Jan 13, 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.

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Imerslund-Grasbeck syndrome

Benign:1

Jan 23, 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

Benign

0.075

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

3.0

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.060

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

0.16

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.1

REVEL

Benign

0.085

Sift

Benign

0.20

Sift4G

Uncertain

0.014

Vest4

0.14

ClinPred

0.0031

GERP RS

-0.40

Varity_R

0.046

gMVP

0.62

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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