12-25227342-T-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_004985.5(KRAS):c.182A>C(p.Gln61Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KRAS | NM_004985.5 | c.182A>C | p.Gln61Pro | missense_variant | Exon 3 of 5 | ENST00000311936.8 | NP_004976.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152176Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome Cov.: 31
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
RASopathy Uncertain:1
This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 61 of the KRAS protein (p.Gln61Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with undergoing clinical exome sequencing (PMID: 27848944). ClinVar contains an entry for this variant (Variation ID: 375966). 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 KRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 34117033, 35944066). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at