Genetic Variant CUBN:c.489+35A>C (chr10-17123553-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001081.4(CUBN):c.489+35A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0925 in 1,452,092 control chromosomes in the GnomAD database, including 7,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 548 hom., cov: 32)

Exomes 𝑓: 0.095 ( 6907 hom. )

Consequence

CUBN
NM_001081.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0780

Publications

12 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 10-17123553-T-G is Benign according to our data. Variant chr10-17123553-T-G is described in ClinVar as Benign. ClinVar VariationId is 1269839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.201 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUBN	NM_001081.4	MANE Select	c.489+35A>C		intron	N/A	NP_001072.2	O60494

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CUBN	ENST00000377833.10	TSL:1 MANE Select	c.489+35A>C	intron	N/A	ENSP00000367064.4	O60494
CUBN	ENST00000433666.5	TSL:5	c.150+35A>C	intron	N/A	ENSP00000415970.1	H7C480
CUBN	ENST00000377823.1	TSL:3	n.563A>C	non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.0729

AC:

11086

AN:

152158

Hom.:

551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0211

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.0556

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.0239

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.0897

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0960

Gnomad OTH

AF:

0.0707

GnomAD2 exomes

AF:

0.0897

AC:

21615

AN:

241072

AF XY:

0.0980

show subpopulations

Gnomad AFR exome

AF:

0.0221

Gnomad AMR exome

AF:

0.0432

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.0218

Gnomad FIN exome

AF:

0.0874

Gnomad NFE exome

AF:

0.0956

Gnomad OTH exome

AF:

0.0917

GnomAD4 exome

AF:

0.0949

AC:

123297

AN:

1299814

Hom.:

6907

Cov.:

AF XY:

0.0991

AC XY:

64829

AN XY:

653992

show subpopulations

African (AFR)

AF:

0.0215

AC:

655

AN:

30456

American (AMR)

AF:

0.0447

AC:

1948

AN:

43618

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

2905

AN:

24912

East Asian (EAS)

AF:

0.0200

AC:

781

AN:

38992

South Asian (SAS)

AF:

0.198

AC:

16182

AN:

81638

European-Finnish (FIN)

AF:

0.0908

AC:

4818

AN:

53080

Middle Eastern (MID)

AF:

0.106

AC:

579

AN:

5484

European-Non Finnish (NFE)

AF:

0.0933

AC:

90170

AN:

966642

Other (OTH)

AF:

0.0956

AC:

5259

AN:

54992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

4991

9983

14974

19966

24957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3038

6076

9114

12152

15190

<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:

0.0727

AC:

11074

AN:

152278

Hom.:

548

Cov.:

AF XY:

0.0744

AC XY:

5542

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0210

AC:

874

AN:

41580

American (AMR)

AF:

0.0555

AC:

849

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

413

AN:

3472

East Asian (EAS)

AF:

0.0239

AC:

124

AN:

5178

South Asian (SAS)

AF:

0.211

AC:

1019

AN:

4818

European-Finnish (FIN)

AF:

0.0897

AC:

951

AN:

10606

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0960

AC:

6528

AN:

68010

Other (OTH)

AF:

0.0700

AC:

148

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

510

1020

1529

2039

2549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<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:

0.0859

Hom.:

1228

Bravo

AF:

0.0646

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.9

(source)

DANN

Benign

0.67

PhyloP100

0.078

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over