rs45569534

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.8902G>C(p.Glu2968Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,612,224 control chromosomes in the GnomAD database, including 381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 34 hom., cov: 33)

Exomes 𝑓: 0.020 ( 347 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.38

Publications

12 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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=0.00558728).

BP6

Variant 10-16888420-C-G is Benign according to our data. Variant chr10-16888420-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 299392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0157 (2389/152202) while in subpopulation NFE AF = 0.0228 (1548/67986). AF 95% confidence interval is 0.0218. There are 34 homozygotes in GnomAd4. There are 1156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.8902G>C	p.Glu2968Gln	missense	Exon 56 of 67	NP_001072.2	O60494

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.8902G>C	p.Glu2968Gln	missense	Exon 56 of 67	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes

AF:

0.0157

AC:

2390

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00394

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0228

Gnomad OTH

AF:

0.0216

GnomAD2 exomes

AF:

0.0151

AC:

3789

AN:

251174

AF XY:

0.0146

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0198

AC:

28962

AN:

1460022

Hom.:

347

Cov.:

AF XY:

0.0191

AC XY:

13884

AN XY:

726454

show subpopulations

African (AFR)

AF:

0.00350

AC:

117

AN:

33452

American (AMR)

AF:

0.0157

AC:

703

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00379

AC:

AN:

26108

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39622

South Asian (SAS)

AF:

0.000696

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.0196

AC:

1045

AN:

53334

Middle Eastern (MID)

AF:

0.00677

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0233

AC:

25839

AN:

1110472

Other (OTH)

AF:

0.0175

AC:

1058

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1225

2450

3674

4899

6124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

956

1912

2868

3824

4780

<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:

0.0157

AC:

2389

AN:

152202

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1156

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00392

AC:

163

AN:

41530

American (AMR)

AF:

0.0215

AC:

329

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0253

AC:

268

AN:

10608

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0228

AC:

1548

AN:

67986

Other (OTH)

AF:

0.0213

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

124

248

372

496

620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0193

Hom.:

Bravo

AF:

0.0156

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0231

AC:

199

ExAC

AF:

0.0154

AC:

1864

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0222

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Imerslund-Grasbeck syndrome (1)

Imerslund-Grasbeck syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.3

PhyloP100

2.4

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.36

Sift

Benign

0.046

Sift4G

Benign

0.086

Polyphen

0.17

Vest4

0.12

MPC

0.19

ClinPred

0.020

GERP RS

5.9

Varity_R

0.36

gMVP

0.79

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over