dbSNP rs1801224: CUBN:p.Pro389Thr (chr10-17105522-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001081.4(CUBN):c.1165C>A(p.Pro389Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,606,728 control chromosomes in the GnomAD database, including 346,564 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26604 hom., cov: 31)

Exomes 𝑓: 0.66 ( 319960 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.12

Publications

37 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=4.6242126E-6).

BP6

Variant 10-17105522-G-T is Benign according to our data. Variant chr10-17105522-G-T is described in ClinVar as Benign. ClinVar VariationId is 299527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

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.1165C>A	p.Pro389Thr	missense	Exon 11 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.1165C>A	p.Pro389Thr	missense	Exon 11 of 67	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes

AF:

0.580

AC:

88001

AN:

151784

Hom.:

26589

Cov.:

show subpopulations

Gnomad AFR

AF:

0.409

Gnomad AMI

AF:

0.604

Gnomad AMR

AF:

0.619

Gnomad ASJ

AF:

0.539

Gnomad EAS

AF:

0.671

Gnomad SAS

AF:

0.532

Gnomad FIN

AF:

0.577

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.674

Gnomad OTH

AF:

0.567

GnomAD2 exomes

AF:

0.618

AC:

155345

AN:

251400

AF XY:

0.616

show subpopulations

Gnomad AFR exome

AF:

0.402

Gnomad AMR exome

AF:

0.637

Gnomad ASJ exome

AF:

0.530

Gnomad EAS exome

AF:

0.668

Gnomad FIN exome

AF:

0.592

Gnomad NFE exome

AF:

0.666

Gnomad OTH exome

AF:

0.613

GnomAD4 exome

AF:

0.659

AC:

958980

AN:

1454828

Hom.:

319960

Cov.:

AF XY:

0.655

AC XY:

474204

AN XY:

724130

show subpopulations

African (AFR)

AF:

0.396

AC:

13208

AN:

33350

American (AMR)

AF:

0.633

AC:

28317

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.532

AC:

13886

AN:

26088

East Asian (EAS)

AF:

0.644

AC:

25531

AN:

39638

South Asian (SAS)

AF:

0.545

AC:

46918

AN:

86126

European-Finnish (FIN)

AF:

0.595

AC:

31781

AN:

53398

Middle Eastern (MID)

AF:

0.534

AC:

3074

AN:

5760

European-Non Finnish (NFE)

AF:

0.686

AC:

758200

AN:

1105586

Other (OTH)

AF:

0.633

AC:

38065

AN:

60166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

15774

31548

47321

63095

78869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19278

38556

57834

77112

96390

<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:

0.580

AC:

88054

AN:

151900

Hom.:

26604

Cov.:

AF XY:

0.577

AC XY:

42842

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.409

AC:

16933

AN:

41396

American (AMR)

AF:

0.620

AC:

9468

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.539

AC:

1867

AN:

3466

East Asian (EAS)

AF:

0.670

AC:

3453

AN:

5152

South Asian (SAS)

AF:

0.531

AC:

2555

AN:

4812

European-Finnish (FIN)

AF:

0.577

AC:

6081

AN:

10542

Middle Eastern (MID)

AF:

0.483

AC:

142

AN:

294

European-Non Finnish (NFE)

AF:

0.674

AC:

45809

AN:

67956

Other (OTH)

AF:

0.566

AC:

1195

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1786

3572

5357

7143

8929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.635

Hom.:

79945

Bravo

AF:

0.575

TwinsUK

AF:

0.699

AC:

2591

ALSPAC

AF:

0.690

AC:

2660

ESP6500AA

AF:

0.413

AC:

1819

ESP6500EA

AF:

0.677

AC:

5823

ExAC

AF:

0.614

AC:

74483

Asia WGS

AF:

0.610

AC:

2120

AN:

3478

EpiCase

AF:

0.647

EpiControl

AF:

0.646

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Imerslund-Grasbeck syndrome type 1 (2)

not provided (2)

Imerslund-Grasbeck syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0000046

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

PhyloP100

3.1

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-5.3

REVEL

Benign

0.098

Sift

Uncertain

0.029

Sift4G

Uncertain

0.012

Polyphen

0.67

Vest4

0.14

MPC

0.30

ClinPred

0.051

GERP RS

1.4

Varity_R

0.086

gMVP

0.39

Mutation Taster

=94/6

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