rs121434430
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_001081.4(CUBN):c.3890C>T(p.Pro1297Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,404 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001081.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 151964Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000330 AC: 83AN: 251280Hom.: 0 AF XY: 0.000324 AC XY: 44AN XY: 135810
GnomAD4 exome AF: 0.000153 AC: 224AN: 1461440Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 105AN XY: 727036
GnomAD4 genome AF: 0.000243 AC: 37AN: 151964Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26AN XY: 74196
ClinVar
Submissions by phenotype
Imerslund-Grasbeck syndrome Pathogenic:2
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1297 of the CUBN protein (p.Pro1297Leu). This variant is present in population databases (rs121434430, gnomAD 0.3%). This missense change has been observed in individuals with megaloblastic anemia 1 (PMID: 7573042, 10080186). It is commonly reported in individuals of Finn ancestry (PMID: 7573042, 10080186). ClinVar contains an entry for this variant (Variation ID: 6689). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CUBN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CUBN function (PMID: 10887099, 24156255). For these reasons, this variant has been classified as Pathogenic. -
- -
Imerslund-Grasbeck syndrome type 1;C5394384:Proteinuria, chronic benign Pathogenic:1
- -
Imerslund-Grasbeck syndrome type 1 Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at