rs3740165

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001081.4(CUBN):c.7662A>G(p.Pro2554Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,614,024 control chromosomes in the GnomAD database, including 3,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 864 hom., cov: 32)

Exomes 𝑓: 0.042 ( 2139 hom. )

Consequence

CUBN
NM_001081.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.727

Publications

16 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:

ENSG00000296126 (HGNC:):

ENSG00000296126 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 10-16907551-T-C is Benign according to our data. Variant chr10-16907551-T-C is described in ClinVar as [Benign]. Clinvar id is 299420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.727 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4 link	c.7662A>G	p.Pro2554Pro	synonymous_variant	Exon 49 of 67	ENST00000377833.10	NP_001072.2	O60494

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 link	c.7662A>G	p.Pro2554Pro	synonymous_variant	Exon 49 of 67	1	NM_001081.4	ENSP00000367064.4		O60494

Frequencies

GnomAD3 genomes

AF:

0.0816

AC:

12417

AN:

152118

Hom.:

860

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0402

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.0559

Gnomad FIN

AF:

0.0350

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0348

Gnomad OTH

AF:

0.0722

GnomAD2 exomes

AF:

0.0539

AC:

13551

AN:

251476

AF XY:

0.0506

show subpopulations

Gnomad AFR exome

AF:

0.187

Gnomad AMR exome

AF:

0.0281

Gnomad ASJ exome

AF:

0.0395

Gnomad EAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.0363

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0451

GnomAD4 exome

AF:

0.0421

AC:

61554

AN:

1461788

Hom.:

2139

Cov.:

AF XY:

0.0417

AC XY:

30288

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.194

AC:

6500

AN:

33476

American (AMR)

AF:

0.0305

AC:

1362

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0403

AC:

1052

AN:

26136

East Asian (EAS)

AF:

0.161

AC:

6392

AN:

39698

South Asian (SAS)

AF:

0.0456

AC:

3930

AN:

86250

European-Finnish (FIN)

AF:

0.0352

AC:

1878

AN:

53418

Middle Eastern (MID)

AF:

0.0649

AC:

373

AN:

5744

European-Non Finnish (NFE)

AF:

0.0331

AC:

36830

AN:

1111952

Other (OTH)

AF:

0.0536

AC:

3237

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3167

6334

9501

12668

15835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0818

AC:

12450

AN:

152236

Hom.:

864

Cov.:

AF XY:

0.0809

AC XY:

6024

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.187

AC:

7775

AN:

41522

American (AMR)

AF:

0.0401

AC:

614

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0418

AC:

145

AN:

3472

East Asian (EAS)

AF:

0.139

AC:

720

AN:

5166

South Asian (SAS)

AF:

0.0562

AC:

271

AN:

4826

European-Finnish (FIN)

AF:

0.0350

AC:

372

AN:

10620

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0348

AC:

2367

AN:

68014

Other (OTH)

AF:

0.0747

AC:

158

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

566

1132

1697

2263

2829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0539

Hom.:

649

Bravo

AF:

0.0875

Asia WGS

AF:

0.107

AC:

371

AN:

3478

EpiCase

AF:

0.0370

EpiControl

AF:

0.0405

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Imerslund-Grasbeck syndrome

Benign:1

Feb 02, 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

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.012

(source)

DANN

Benign

0.52

PhyloP100

-0.73

Mutation Taster

=100/0

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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rs3740165

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