Genetic Variant CUBN:c.8598+3220G>A (chr10-16895776-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001081.4(CUBN):c.8598+3220G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,048 control chromosomes in the GnomAD database, including 825 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 825 hom., cov: 32)

Consequence

CUBN
NM_001081.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.168

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CUBN	NM_001081.4 link	c.8598+3220G>A	intron_variant	Intron 54 of 66	ENST00000377833.10	NP_001072.2
CUBN	XM_011519709.3 link	c.4584+3220G>A	intron_variant	Intron 28 of 40		XP_011518011.1
CUBN	XM_011519710.3 link	c.4560+3220G>A	intron_variant	Intron 28 of 40		XP_011518012.1
CUBN	XM_011519711.4 link	c.4440+3220G>A	intron_variant	Intron 27 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CUBN	ENST00000377833.10 link	c.8598+3220G>A	intron_variant	Intron 54 of 66	1	NM_001081.4	ENSP00000367064.4
ENSG00000296126	ENST00000736661.1 link	n.195+3142C>T	intron_variant	Intron 2 of 3
ENSG00000296126	ENST00000736662.1 link	n.100+4165C>T	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15646

AN:

151930

Hom.:

819

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.0898

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0788

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.116

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

GnomAD4 genome

AF:

0.103

AC:

15676

AN:

152048

Hom.:

825

Cov.:

AF XY:

0.100

AC XY:

7468

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.120

AC:

4961

AN:

41452

American (AMR)

AF:

0.0897

AC:

1370

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

532

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5174

South Asian (SAS)

AF:

0.114

AC:

551

AN:

4820

European-Finnish (FIN)

AF:

0.0788

AC:

833

AN:

10572

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.103

AC:

7025

AN:

67972

Other (OTH)

AF:

0.114

AC:

241

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

720

1439

2159

2878

3598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<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:

0.0501

Hom.:

Bravo

AF:

0.104

Asia WGS

AF:

0.0640

AC:

224

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

3.3

(source)

DANN

Benign

0.60

PhyloP100

0.17

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over