Genetic Variant CUBN:c.8755+174T>A (chr10-16890197-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001081.4(CUBN):c.8755+174T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0818 in 152,044 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.082 ( 563 hom., cov: 31)

Consequence

CUBN
NM_001081.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.694

Publications

5 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 10-16890197-A-T is Benign according to our data. Variant chr10-16890197-A-T is described in ClinVar as Benign. ClinVar VariationId is 1290271.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.8755+174T>A		intron	N/A	NP_001072.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	ENST00000377833.10	TSL:1 MANE Select	c.8755+174T>A		intron	N/A	ENSP00000367064.4

Frequencies

GnomAD3 genomes

AF:

0.0819

AC:

12437

AN:

151926

Hom.:

562

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0441

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.0807

Gnomad ASJ

AF:

0.149

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.0781

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0931

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0818

AC:

12433

AN:

152044

Hom.:

563

Cov.:

AF XY:

0.0798

AC XY:

5931

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0441

AC:

1828

AN:

41446

American (AMR)

AF:

0.0806

AC:

1232

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

518

AN:

3472

East Asian (EAS)

AF:

0.00175

AC:

AN:

5156

South Asian (SAS)

AF:

0.122

AC:

588

AN:

4812

European-Finnish (FIN)

AF:

0.0781

AC:

826

AN:

10576

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7094

AN:

67986

Other (OTH)

AF:

0.0912

AC:

192

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

575

1151

1726

2302

2877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0935

Hom.:

101

Bravo

AF:

0.0787

Asia WGS

AF:

0.0590

AC:

206

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.18

(source)

DANN

Benign

0.43

PhyloP100

-0.69

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over