rs769747844
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001081.4(CUBN):c.7390A>C(p.Thr2464Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
CUBN
NM_001081.4 missense
NM_001081.4 missense
Scores
2
3
14
Clinical Significance
Conservation
PhyloP100: 0.315
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.31146842).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CUBN | NM_001081.4 | c.7390A>C | p.Thr2464Pro | missense_variant | 48/67 | ENST00000377833.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CUBN | ENST00000377833.10 | c.7390A>C | p.Thr2464Pro | missense_variant | 48/67 | 1 | NM_001081.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152068Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251348Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135854
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727238
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74284
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Imerslund-Grasbeck syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 581546). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. This variant is present in population databases (rs769747844, gnomAD 0.06%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2464 of the CUBN protein (p.Thr2464Pro). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Loss of phosphorylation at T2464 (P = 0.0447);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at