10-16982616-A-T

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.4563T>A(p.Ile1521Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,612,786 control chromosomes in the GnomAD database, including 587,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 43738 hom., cov: 32)

Exomes 𝑓: 0.86 ( 544048 hom. )

Consequence

CUBN
NM_001081.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.65

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: 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:

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=-0.51).

BP6

Variant 10-16982616-A-T is Benign according to our data. Variant chr10-16982616-A-T is described in ClinVar as Benign. ClinVar VariationId is 299480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.65 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4 link	c.4563T>A	p.Ile1521Ile	synonymous_variant	Exon 31 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.4563T>A	p.Ile1521Ile	synonymous_variant	Exon 31 of 67	1	NM_001081.4	ENSP00000367064.4		O60494
CUBN	ENST00000438254.1 link	n.129T>A		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111487

AN:

151936

Hom.:

43739

Cov.:

show subpopulations

Gnomad AFR

AF:

0.456

Gnomad AMI

AF:

0.986

Gnomad AMR

AF:

0.702

Gnomad ASJ

AF:

0.825

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.785

Gnomad FIN

AF:

0.851

Gnomad MID

AF:

0.829

Gnomad NFE

AF:

0.893

Gnomad OTH

AF:

0.767

GnomAD2 exomes

AF:

0.770

AC:

193439

AN:

251130

AF XY:

0.789

show subpopulations

Gnomad AFR exome

AF:

0.447

Gnomad AMR exome

AF:

0.559

Gnomad ASJ exome

AF:

0.824

Gnomad EAS exome

AF:

0.541

Gnomad FIN exome

AF:

0.850

Gnomad NFE exome

AF:

0.889

Gnomad OTH exome

AF:

0.815

GnomAD4 exome

AF:

0.856

AC:

1249822

AN:

1460732

Hom.:

544048

Cov.:

AF XY:

0.857

AC XY:

622493

AN XY:

726774

show subpopulations

African (AFR)

AF:

0.437

AC:

14610

AN:

33460

American (AMR)

AF:

0.574

AC:

25656

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.826

AC:

21581

AN:

26126

East Asian (EAS)

AF:

0.501

AC:

19894

AN:

39678

South Asian (SAS)

AF:

0.796

AC:

68646

AN:

86218

European-Finnish (FIN)

AF:

0.854

AC:

45521

AN:

53302

Middle Eastern (MID)

AF:

0.815

AC:

4695

AN:

5764

European-Non Finnish (NFE)

AF:

0.900

AC:

999504

AN:

1111122

Other (OTH)

AF:

0.824

AC:

49715

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

8273

16546

24819

33092

41365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21222

42444

63666

84888

106110

<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:

0.733

AC:

111518

AN:

152054

Hom.:

43738

Cov.:

AF XY:

0.731

AC XY:

54309

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.456

AC:

18900

AN:

41446

American (AMR)

AF:

0.701

AC:

10712

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.825

AC:

2863

AN:

3470

East Asian (EAS)

AF:

0.533

AC:

2746

AN:

5154

South Asian (SAS)

AF:

0.786

AC:

3780

AN:

4812

European-Finnish (FIN)

AF:

0.851

AC:

9020

AN:

10600

Middle Eastern (MID)

AF:

0.827

AC:

243

AN:

294

European-Non Finnish (NFE)

AF:

0.893

AC:

60735

AN:

67982

Other (OTH)

AF:

0.768

AC:

1620

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1230

2460

3691

4921

6151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.840

Hom.:

17739

Bravo

AF:

0.703

Asia WGS

AF:

0.661

AC:

2303

AN:

3478

EpiCase

AF:

0.887

EpiControl

AF:

0.888

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1

Benign:2

Jan 12, 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. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Imerslund-Grasbeck syndrome

Benign:1

Feb 03, 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

-0.51

CADD

Benign

8.1

(source)

DANN

Benign

0.78

PhyloP100

1.6

Mutation Taster

=100/0

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

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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