Genetic Variant CUBN:c.9454+6135G>A (chr10-16863501-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.9454+6135G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,082 control chromosomes in the GnomAD database, including 4,415 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 0.22 ( 4415 hom., cov: 32)

Consequence

CUBN
NM_001081.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.334

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: 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CUBN	NM_001081.4 link	c.9454+6135G>A	intron_variant	Intron 59 of 66	ENST00000377833.10	NP_001072.2	O60494
CUBN	XM_011519709.3 link	c.5440+6135G>A	intron_variant	Intron 33 of 40		XP_011518011.1
CUBN	XM_011519710.3 link	c.5416+6135G>A	intron_variant	Intron 33 of 40		XP_011518012.1
CUBN	XM_011519711.4 link	c.5296+6135G>A	intron_variant	Intron 32 of 39		XP_011518013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUBN	ENST00000377833.10 link	c.9454+6135G>A		intron_variant	Intron 59 of 66	1	NM_001081.4	ENSP00000367064.4		O60494
CUBN	ENST00000649135.1 link	n.49+3306G>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33503

AN:

151964

Hom.:

4405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.293

Gnomad AMR

AF:

0.357

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.609

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.179

Gnomad OTH

AF:

0.248

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

GnomAD4 genome

AF:

0.221

AC:

33538

AN:

152082

Hom.:

4415

Cov.:

AF XY:

0.230

AC XY:

17114

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.176

AC:

7303

AN:

41478

American (AMR)

AF:

0.357

AC:

5459

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

757

AN:

3468

East Asian (EAS)

AF:

0.609

AC:

3149

AN:

5168

South Asian (SAS)

AF:

0.346

AC:

1668

AN:

4824

European-Finnish (FIN)

AF:

0.205

AC:

2169

AN:

10560

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.179

AC:

12175

AN:

67986

Other (OTH)

AF:

0.254

AC:

536

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1275

2551

3826

5102

6377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.204

Hom.:

5366

Bravo

AF:

0.235

Asia WGS

AF:

0.432

AC:

1502

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.93

(source)

DANN

Benign

0.64

PhyloP100

-0.33

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over