rs138083522

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.2594G>A(p.Ser865Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,613,902 control chromosomes in the GnomAD database, including 84 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 83 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.871

Publications

7 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=0.0062994957).

BP6

Variant 10-17071457-C-T is Benign according to our data. Variant chr10-17071457-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 265086.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 = 0.00734 (1117/152208) while in subpopulation NFE AF = 0.0123 (834/68028). AF 95% confidence interval is 0.0116. There are 1 homozygotes in GnomAd4. There are 529 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 83 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.2594G>A	p.Ser865Asn	missense	Exon 19 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.2594G>A	p.Ser865Asn	missense	Exon 19 of 67	ENSP00000367064.4	O60494

Frequencies

GnomAD3 genomes

AF:

0.00734

AC:

1117

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00520

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.00862

GnomAD2 exomes

AF:

0.00730

AC:

1835

AN:

251288

AF XY:

0.00764

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00307

Gnomad ASJ exome

AF:

0.00843

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.00946

GnomAD4 exome

AF:

0.00969

AC:

14170

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00977

AC XY:

7102

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33478

American (AMR)

AF:

0.00333

AC:

149

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00911

AC:

238

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00512

AC:

442

AN:

86256

European-Finnish (FIN)

AF:

0.00618

AC:

330

AN:

53408

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0112

AC:

12400

AN:

1111870

Other (OTH)

AF:

0.00861

AC:

520

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

772

1545

2317

3090

3862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.00734

AC:

1117

AN:

152208

Hom.:

Cov.:

AF XY:

0.00711

AC XY:

529

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00210

AC:

AN:

41518

American (AMR)

AF:

0.00353

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00520

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

834

AN:

68028

Other (OTH)

AF:

0.00853

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

118

176

235

294

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:

0.0101

Hom.:

Bravo

AF:

0.00716

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0117

AC:

101

ExAC

AF:

0.00745

AC:

904

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.00942

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)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.29

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.026

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0063

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

PhyloP100

-0.87

PrimateAI

Benign

0.32

PROVEAN

Benign

0.38

REVEL

Benign

0.062

Sift

Benign

0.54

Sift4G

Benign

0.58

Polyphen

0.0070

Vest4

0.66

MVP

0.23

MPC

0.077

ClinPred

0.0011

GERP RS

-4.3

Varity_R

0.051

gMVP

0.20

Mutation Taster

=94/6

polymorphism

(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