10-16824206-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001081.4(CUBN):​c.*769G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 152,224 control chromosomes in the GnomAD database, including 3 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 0.0031 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CUBN
NM_001081.4 3_prime_UTR

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.305

Publications

1 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

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=-0.86).
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00309 (471/152224) while in subpopulation AFR AF = 0.011 (458/41540). AF 95% confidence interval is 0.0102. There are 3 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CUBNNM_001081.4 linkc.*769G>A 3_prime_UTR_variant Exon 67 of 67 ENST00000377833.10 NP_001072.2 O60494
CUBNXM_011519709.3 linkc.*769G>A 3_prime_UTR_variant Exon 41 of 41 XP_011518011.1
CUBNXM_011519710.3 linkc.*769G>A 3_prime_UTR_variant Exon 41 of 41 XP_011518012.1
CUBNXM_011519711.4 linkc.*769G>A 3_prime_UTR_variant Exon 40 of 40 XP_011518013.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CUBNENST00000377833.10 linkc.*769G>A 3_prime_UTR_variant Exon 67 of 67 1 NM_001081.4 ENSP00000367064.4 O60494

Frequencies

GnomAD3 genomes
AF:
0.00310
AC:
472
AN:
152106
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0111
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00143
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
160
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
90
African (AFR)
AC:
0
AN:
0
American (AMR)
AF:
0.00
AC:
0
AN:
2
Ashkenazi Jewish (ASJ)
AC:
0
AN:
0
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4
European-Finnish (FIN)
AC:
0
AN:
0
Middle Eastern (MID)
AC:
0
AN:
0
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
146
Other (OTH)
AF:
0.00
AC:
0
AN:
4
GnomAD4 genome
AF:
0.00309
AC:
471
AN:
152224
Hom.:
3
Cov.:
32
AF XY:
0.00280
AC XY:
208
AN XY:
74408
show subpopulations
African (AFR)
AF:
0.0110
AC:
458
AN:
41540
American (AMR)
AF:
0.000654
AC:
10
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5164
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68016
Other (OTH)
AF:
0.00142
AC:
3
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
23
45
68
90
113
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
10
20
30
40
50
<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:
0.00250
Hom.:
0
Bravo
AF:
0.00337
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Imerslund-Grasbeck syndrome type 1 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
CADD
Benign
1.6
DANN
Benign
0.65
PhyloP100
0.30
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs149618660; hg19: chr10-16866205; API