rs397517043
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP5
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.531_533delGAA (p.Lys180del) variant in the KRAS gene is 0.51% for European (non-Finnish) chromosomes by the Exome Aggregation Consortium (55/64754 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR ID's: 21766, 26957; ClinVar SCV000061947, SCV000207865). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA135584/MONDO:0021060/004
Frequency
Consequence
NM_004985.5 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRAS | NM_004985.5 | c.531_533del | p.Lys180del | inframe_deletion | 5/5 | ENST00000311936.8 | |
KRAS | NM_033360.4 | c.*85_*87del | 3_prime_UTR_variant | 6/6 | ENST00000256078.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRAS | ENST00000311936.8 | c.531_533del | p.Lys180del | inframe_deletion | 5/5 | 1 | NM_004985.5 | P4 | |
KRAS | ENST00000256078.10 | c.*85_*87del | 3_prime_UTR_variant | 6/6 | 1 | NM_033360.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000683 AC: 104AN: 152180Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000573 AC: 143AN: 249744Hom.: 0 AF XY: 0.000578 AC XY: 78AN XY: 135056
GnomAD4 exome AF: 0.00112 AC: 1628AN: 1458460Hom.: 2 AF XY: 0.00109 AC XY: 788AN XY: 725740
GnomAD4 genome ? AF: 0.000683 AC: 104AN: 152298Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36AN XY: 74480
ClinVar
Submissions by phenotype
not provided Benign:6
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 21, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | KRAS: PM4:Supporting, BS1 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
RASopathy Benign:2
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The filtering allele frequency of the c.531_533delGAA (p.Lys180del) variant in the KRAS gene is 0.51% for European (non-Finnish) chromosomes by the Exome Aggregation Consortium (55/64754 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR ID's: 21766, 26957; ClinVar SCV000061947, SCV000207865). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not specified Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2017 | p.Lys180del in exon 6 of KRAS: This variant is not expected to have clinical sig nificance because it has been identified in 0.1% (123/125888) European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517043). In addition, it was identified in one individual with featu res of Noonan syndrome who also carried a pathogenic variant in KRAS, which was sufficient to explain their phenotype, and in two parents, one whose disease sta tus was unknown and the other who was unaffected (LMM unpublished data). This va riant causes an in-frame deletion of the amino acid lysine (Lys) at position 180 . This amino acid is in a stretch of six lysine (Lys) residues. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
KRAS-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 30, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 08, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Noonan syndrome and Noonan-related syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 25, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at