12-25227345-C-T
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_004985.5(KRAS):c.179G>A(p.Gly60Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G60R) has been classified as Pathogenic.
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
Publications
- cardiofaciocutaneous syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- cardiofaciocutaneous syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
- linear nevus sebaceous syndromeInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KRAS | NM_004985.5 | c.179G>A | p.Gly60Asp | missense_variant | Exon 3 of 5 | ENST00000311936.8 | NP_004976.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727214 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29493581, 17875937) -
not specified Uncertain:1
Variant summary: KRAS c.179G>A (p.Gly60Asp) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251328 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although reported in settings of somatic cancers (example, COSMIC database), to our knowledge, no germline occurrence of c.179G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at