rs1801230

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001081.4(CUBN):​c.10265C>T​(p.Thr3422Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,004 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 29 hom., cov: 33)
Exomes 𝑓: 0.024 ( 479 hom. )

Consequence

CUBN
NM_001081.4 missense

Scores

3
15

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009336919).
BP6
Variant 10-16835111-G-A is Benign according to our data. Variant chr10-16835111-G-A is described in ClinVar as [Benign]. Clinvar id is 299364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-16835111-G-A is described in Lovd as [Benign]. Variant chr10-16835111-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2539/152218) while in subpopulation NFE AF= 0.0271 (1842/68002). AF 95% confidence interval is 0.0261. There are 29 homozygotes in gnomad4. There are 1168 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CUBNNM_001081.4 linkuse as main transcriptc.10265C>T p.Thr3422Ile missense_variant 64/67 ENST00000377833.10 NP_001072.2 O60494
CUBNXM_011519709.3 linkuse as main transcriptc.6251C>T p.Thr2084Ile missense_variant 38/41 XP_011518011.1
CUBNXM_011519710.3 linkuse as main transcriptc.6227C>T p.Thr2076Ile missense_variant 38/41 XP_011518012.1
CUBNXM_011519711.4 linkuse as main transcriptc.6107C>T p.Thr2036Ile missense_variant 37/40 XP_011518013.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CUBNENST00000377833.10 linkuse as main transcriptc.10265C>T p.Thr3422Ile missense_variant 64/671 NM_001081.4 ENSP00000367064.4 O60494

Frequencies

GnomAD3 genomes
AF:
0.0167
AC:
2539
AN:
152100
Hom.:
29
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00466
Gnomad AMI
AF:
0.0439
Gnomad AMR
AF:
0.0109
Gnomad ASJ
AF:
0.0332
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00435
Gnomad FIN
AF:
0.0112
Gnomad MID
AF:
0.0382
Gnomad NFE
AF:
0.0271
Gnomad OTH
AF:
0.0139
GnomAD3 exomes
AF:
0.0175
AC:
4406
AN:
251256
Hom.:
63
AF XY:
0.0179
AC XY:
2425
AN XY:
135776
show subpopulations
Gnomad AFR exome
AF:
0.00535
Gnomad AMR exome
AF:
0.00824
Gnomad ASJ exome
AF:
0.0334
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00451
Gnomad FIN exome
AF:
0.0136
Gnomad NFE exome
AF:
0.0279
Gnomad OTH exome
AF:
0.0165
GnomAD4 exome
AF:
0.0240
AC:
35145
AN:
1461786
Hom.:
479
Cov.:
32
AF XY:
0.0235
AC XY:
17103
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00487
Gnomad4 AMR exome
AF:
0.00894
Gnomad4 ASJ exome
AF:
0.0357
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00485
Gnomad4 FIN exome
AF:
0.0125
Gnomad4 NFE exome
AF:
0.0279
Gnomad4 OTH exome
AF:
0.0235
GnomAD4 genome
AF:
0.0167
AC:
2539
AN:
152218
Hom.:
29
Cov.:
33
AF XY:
0.0157
AC XY:
1168
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.00467
Gnomad4 AMR
AF:
0.0109
Gnomad4 ASJ
AF:
0.0332
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00415
Gnomad4 FIN
AF:
0.0112
Gnomad4 NFE
AF:
0.0271
Gnomad4 OTH
AF:
0.0142
Alfa
AF:
0.0252
Hom.:
79
Bravo
AF:
0.0177
TwinsUK
AF:
0.0297
AC:
110
ALSPAC
AF:
0.0327
AC:
126
ESP6500AA
AF:
0.00658
AC:
29
ESP6500EA
AF:
0.0288
AC:
248
ExAC
AF:
0.0183
AC:
2224
Asia WGS
AF:
0.00404
AC:
14
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 01, 2023- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 26, 2020This variant is associated with the following publications: (PMID: 26827111) -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024CUBN: BP4, BS1, BS2 -
Imerslund-Grasbeck syndrome type 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Imerslund-Grasbeck syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
9.4
DANN
Uncertain
0.98
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.27
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.42
T
MetaRNN
Benign
0.0093
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
0.98
N
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-2.9
D
REVEL
Benign
0.098
Sift
Benign
0.34
T
Sift4G
Benign
0.11
T
Polyphen
0.70
P
Vest4
0.074
MPC
0.13
ClinPred
0.035
T
GERP RS
3.9
Varity_R
0.084
gMVP
0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1801230; hg19: chr10-16877110; COSMIC: COSV64715751; API