rs3740168

Variant names:

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.7724C>G(p.Pro2575Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,613,304 control chromosomes in the GnomAD database, including 1,387 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P2575P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.025 ( 148 hom., cov: 32)

Exomes 𝑓: 0.026 ( 1239 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.81

Publications

17 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:

ENSG00000296126 (HGNC:):

ENSG00000296126 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=0.0017643869).

BP6

Variant 10-16906391-G-C is Benign according to our data. Variant chr10-16906391-G-C is described in ClinVar as Benign. ClinVar VariationId is 299419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 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.7724C>G	p.Pro2575Arg	missense	Exon 50 of 67	NP_001072.2	O60494

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUBN	ENST00000377833.10	TSL:1 MANE Select	c.7724C>G	p.Pro2575Arg	missense	Exon 50 of 67	ENSP00000367064.4	O60494
CUBN	ENST00000648092.1		n.260C>G		non_coding_transcript_exon	Exon 2 of 4
CUBN	ENST00000649933.1		n.86C>G		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3745

AN:

152118

Hom.:

148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.0587

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0447

AC:

11231

AN:

251168

AF XY:

0.0443

show subpopulations

Gnomad AFR exome

AF:

0.00622

Gnomad AMR exome

AF:

0.0972

Gnomad ASJ exome

AF:

0.0155

Gnomad EAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0354

GnomAD4 exome

AF:

0.0260

AC:

37915

AN:

1461068

Hom.:

1239

Cov.:

AF XY:

0.0274

AC XY:

19932

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.00616

AC:

206

AN:

33464

American (AMR)

AF:

0.0910

AC:

4068

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

362

AN:

26128

East Asian (EAS)

AF:

0.130

AC:

5152

AN:

39680

South Asian (SAS)

AF:

0.0919

AC:

7919

AN:

86212

European-Finnish (FIN)

AF:

0.0102

AC:

543

AN:

53416

Middle Eastern (MID)

AF:

0.0533

AC:

307

AN:

5762

European-Non Finnish (NFE)

AF:

0.0157

AC:

17435

AN:

1111342

Other (OTH)

AF:

0.0319

AC:

1923

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1965

3929

5894

7858

9823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

852

1704

2556

3408

4260

<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:

0.0246

AC:

3745

AN:

152236

Hom.:

148

Cov.:

AF XY:

0.0269

AC XY:

2002

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00638

AC:

265

AN:

41552

American (AMR)

AF:

0.0587

AC:

897

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.136

AC:

704

AN:

5168

South Asian (SAS)

AF:

0.100

AC:

483

AN:

4824

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10610

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0159

AC:

1083

AN:

68012

Other (OTH)

AF:

0.0313

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

177

355

532

710

887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0196

Hom.:

Bravo

AF:

0.0289

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0148

AC:

127

ExAC

AF:

0.0420

AC:

5103

Asia WGS

AF:

0.102

AC:

354

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0206

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Imerslund-Grasbeck syndrome type 1 (2)

Imerslund-Grasbeck syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.6

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.024

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.0

PhyloP100

1.8

PrimateAI

Benign

0.33

PROVEAN

Benign

0.26

REVEL

Benign

0.059

Sift

Benign

0.20

Sift4G

Uncertain

0.027

Polyphen

0.14

Vest4

0.034

MPC

0.088

ClinPred

0.0061

GERP RS

4.6

Varity_R

0.026

gMVP

0.38

Mutation Taster

=88/12

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