About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.-11-30T>C, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen KRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
RASopathy VCEP BP4 (Supporting) applies to splicing variants for which the predicted outcome is negligible. SpliceAI predicts no significant splice impact for NM_033360.4:c.-11-30T>C (max delta score = 0.01), well below any threshold for splice-altering prediction.
BP7Supporting
BP7 · supporting
RASopathy VCEP BP7 (Supporting) applies to intronic positions (excluding canonical splice sites) when splicing prediction algorithms predict no splice impact AND the nucleotide is not highly conserved. This variant resides in intron 1, SpliceAI predicts no splice impact (max delta = 0.01), and the variant is observed in gnomAD (8 alleles in v2.1, predominantly East Asian), consistent with a position that tolerates variation and is not under strong purifying selection.
Recorded classification: Likely benign
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting, BP7 supporting; maps to Likely Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
11 / 1,561,408 alleles
gnomAD v4.1: 11 / 1,561,408 alleles. Recorded AF 7.04492e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.74087e-05; MAF= 0.00374%, 8/213854 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000473805; MAF= 0.04738%, 7/14774 alleles, homozygotes = 0); grpmax FAF= 0.00022756.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen KRAS VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 8 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_033360.4:c.-11-30T>C is a deep intronic substitution in intron 1 of KRAS, 30 nucleotides upstream of the coding region start.
SpliceAI predicts no splice impact (max delta = 0.01), satisfying RASopathy VCEP BP4 (Supporting) for a negligible splicing outcome.
The variant satisfies RASopathy VCEP BP7 (Supporting) as an intronic variant with no predicted splice impact and evidence of standing variation in gnomAD (8/213,854 alleles in v2.1, predominantly East Asian), indicating the nucleotide is not highly conserved.
Population frequency in gnomAD (grpmax FAF 0.0228% v2.1) falls below both the BS1 threshold (0.025%) and the BA1 threshold (0.05%), precluding application of benign population-frequency criteria.
The variant is present in gnomAD, ruling out PM2 (absence from controls). No pathogenic criteria are met.
No publications, functional data, ClinVar entries, de novo reports, segregation data, or proband-level clinical information exist for this variant.
Under the RASopathy VCEP v2.3.0 scoring framework, two supporting benign criteria (BP4 + BP7) are met, which satisfies Rule19 (≥2 Supporting Benign criteria) for a classification of Likely Benign.
No criteria match.
Met · 2
BP4 SupportingRASopathy VCEP BP4 (Supporting) applies to splicing variants for which the predicted outcome is negligible. SpliceAI predicts no significant splice impact for NM_033360.4:c.-11-30T>C (max delta score = 0.01), well below any threshold for splice-altering prediction. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no donor/acceptor gain or loss predicted.
- VCEP BP4 rule: splicing predicted outcome is negligible.
Sources
BP7 SupportingRASopathy VCEP BP7 (Supporting) applies to intronic positions (excluding canonical splice sites) when splicing prediction algorithms predict no splice impact AND the nucleotide is not highly conserved. This variant resides in intron 1, SpliceAI predicts no splice impact (max delta = 0.01), and the variant is observed in gnomAD (8 alleles in v2.1, predominantly East Asian), consistent with a position that tolerates variation and is not under strong purifying selection. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no splice impact predicted.
- gnomAD v2.1: 8/213
- 854 alleles
- present in East Asian population (7/14
- 774).
- VCEP BP7 rule explicitly extends to intronic positions outside canonical splice sites.
Still missing
- Direct phyloP/GERP++ conservation scores not available
- nucleotide conservation inferred from gnomAD population variation data.
Sources
Not met · 5 · evaluated, threshold not reached
PS3 No functional data exists for NM_033360.4:c.-11-30T>C. A comprehensive literature search returned zero publications; the variant has not been tested in any VCEP-approved functional assay (RAS activation, MEK/ERK activation). The variant is deep intronic and falls outside the range of any systematically characterized functional domain. Details ▾Hide ▴
Evidence considered
- Literature search returned 0 PMIDs
- no functional data for this variant.
Still missing
- No publications found.
PM2 RASopathy VCEP PM2 (Supporting) requires the variant to be absent from gnomAD. NM_033360.4:c.-11-30T>C is present in gnomAD v2.1 at 8/213,854 alleles (AF = 0.00374%; grpmax FAF = 0.0228%) and in gnomAD v4.1 at 11/1,561,408 alleles (AF = 0.00070%). The variant is not absent, so PM2 is not satisfied. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 8/213
- 854 alleles
- AF = 0.00374%
- grpmax FAF = 0.0228%
- gnomAD v4.1: 11/1
- 561
- 408 alleles
- AF = 0.00070%
- grpmax FAF = 0.00939%
Sources
PP3 RASopathy VCEP PP3 requires REVEL ≥ 0.7 for missense variants OR a splicing prediction matching the disease mechanism for splicing variants. REVEL is unavailable (intronic variant). SpliceAI predicts no significant splice impact (max delta = 0.01); thus the computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no splice impact predicted.
- REVEL not applicable (intronic variant).
Sources
BA1 RASopathy VCEP BA1 requires gnomAD filtering allele frequency ≥ 0.05%. The grpmax FAF is 0.0228% in v2.1 and 0.00939% in v4.1, both below the 0.05% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF = 0.0228% (< 0.05% threshold)
- gnomAD v4.1 grpmax FAF = 0.00939% (< 0.05% threshold)
Sources
BS1 RASopathy VCEP BS1 requires gnomAD filtering allele frequency ≥ 0.025%. The grpmax FAF is 0.0228% in v2.1, narrowly below the threshold; v4.1 grpmax FAF is 0.00939%, also below. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF = 0.0228% (< 0.025% threshold)
- gnomAD v4.1 grpmax FAF = 0.00939% (< 0.025% threshold)
Still missing
- V2.1 grpmax FAF (0.0228%) is very close to the 0.025% BS1 threshold
- borderline call.
Sources
Not assessed · 8 · no assessment recorded
PS2 No proband-level clinical data, parental testing, or de novo reports are available for this variant. Cannot evaluate PS2 without confirmed de novo occurrence in a RASopathy-affected individual. Details ▾Hide ▴
Still missing
- No proband phenotype or parental genotype data available.
PS4 No proband count, case-control, or enrichment data are available for this variant. RASopathy VCEP PS4 is point-based and requires proband phenotypes; none are provided. Details ▾Hide ▴
Still missing
- No proband or case-control data.
PM6 No de novo observation data (assumed or confirmed) are available for this variant. PM6 requires a de novo occurrence in a proband; none is reported in the literature or provided clinically. Details ▾Hide ▴
Still missing
- No de novo reports.
PP1 No segregation data are available. RASopathy VCEP PP1 requires ≥3 informative meioses for Supporting strength; no family studies have been reported for this variant. Details ▾Hide ▴
Still missing
- No family or segregation data.
BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. No such observation data are available for this variant. Details ▾Hide ▴
Still missing
- No healthy-adult observation data.
BS4 BS4 requires lack of segregation in affected family members; no family data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data.
BP2 BP2 requires observation in trans with a pathogenic variant (for dominant disorders) or in cis with a pathogenic variant, or an alternative molecular cause of RASopathy in the same gene. No such data are available. Details ▾Hide ▴
Still missing
- No trans/cis or alternative molecular cause data.
BP5 BP5 requires an alternative molecular cause of a RASopathy in a different gene, with phenotype consistent with expected severity. No such data are available. Details ▾Hide ▴
Still missing
- No alternative molecular cause data.
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPRASopathy VCEP v2.3.0 designates PVS1 as not applicable for KRAS; the variant NM_033360.4:c.-11-30T>C is a deep intronic substitution and does not fall into any null-variant bucket (nonsense, frameshift, canonical splice site). Details ▾Hide ▴
PS1 N/APS1 requires same amino acid change as a previously established pathogenic variant; NM_033360.4:c.-11-30T>C is a deep intronic substitution with no amino acid consequence. Details ▾Hide ▴
PM1 N/ARASopathy VCEP PM1 applies only to critical functional domains (P-loop AA 10-17, Switch I AA 25-40, Switch II AA 57-64, SAK AA 145-156). NM_033360.4:c.-11-30T>C is a deep intronic variant in intron 1, upstream of all coding sequence, and does not reside within any recognized functional domain. Details ▾Hide ▴
Evidence considered
- VCEP PM1 rule restricts applicability to four named protein domains
- variant is intronic and upstream of all coding sequence.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM3 VCEPPre-determined skip: RASopathies are autosomal dominant; PM3 (recessive, detected in trans) is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APre-determined skip: PM4 applies to in-frame deletions/insertions or stop-loss variants. NM_033360.4:c.-11-30T>C is an intronic substitution, not a protein-length-altering variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a novel missense change at a codon where a different pathogenic missense has been established. NM_033360.4:c.-11-30T>C is a deep intronic substitution with no amino acid consequence; PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant class is intronic
- not missense-like
- PM5 candidate search returned no eligible comparators.
Sources
cspec ↗pm5_candidates
PP2 VCEPRASopathy VCEP designates PP2 as not applicable because the KRAS missense z-score in gnomAD is <3.09. Details ▾Hide ▴
PP4 VCEPRASopathy VCEP designates PP4 as not applicable; phenotype specificity is addressed through PS4 scoring. Details ▾Hide ▴
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; the RASopathy VCEP explicitly marks it as not applicable. Details ▾Hide ▴
Evidence considered
- VCEP PP5: Not Applicable for this VCEP per ClinGen SVI VCEP Review Committee.
Sources
BS3 VCEPRASopathy VCEP designates BS3 as not applicable. Details ▾Hide ▴
BP1 N/ARASopathy VCEP BP1 applies specifically to truncating variants (nonsense, frameshift, canonical splice, initiation codon, exon deletion) in genes where the disease mechanism is gain-of-function. NM_033360.4:c.-11-30T>C is a deep intronic substitution and is not a truncating variant. Details ▾Hide ▴
Evidence considered
- Variant is an intronic substitution
- not a truncating variant
- BP1 not applicable.
Sources
BP3 VCEPPre-determined skip: RASopathy VCEP designates BP3 as not applicable (no known benign repetitive areas in RASopathy genes). Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; the RASopathy VCEP explicitly marks it as not applicable. Details ▾Hide ▴
Evidence considered
- VCEP BP6: Not Applicable for this VCEP per ClinGen SVI VCEP Review Committee.
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_033360.4
- Coding (HGVS c.)
- NM_033360.4:c.-11-30T>C
- Protein (HGVS p.)
- NP_203524.1:p.?
- GRCh38
- chr12:25245425 A>G
- GRCh37
- chr12:25398359 A>G
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_033360.4. Select a row to find it on the plot.
KRASNM_033360.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
11 / 1,561,408 alleles
AF 7.04e-06 · 0 homozygotes · FAF 9.39e-05
gnomAD v2.1
8 / 213,854 alleles
AF 3.74e-05 · 0 homozygotes · FAF 0.000228
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 7e-06 · 11 / 1,561,408 alleles · 0 hom · FAF 9.4e-05
| East Asian8 / 42,334 | 0.00019 |
| South Asian1 / 85,892 | 1.2e-05 |
| European (non-Finnish)2 / 1,147,668 | 1.7e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.7e-05 · 8 / 213,854 alleles · 0 hom · FAF 0.00023
| East Asian7 / 14,774 | 0.00047 |
| South Asian1 / 24,650 | 4.1e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 7.04492e-06; MAF= 0.00070%, 11/1561408 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000188973; MAF= 0.01890%, 8/42334 alleles, homozygotes = 0); grpmax FAF= 9.393e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.74087e-05; MAF= 0.00374%, 8/213854 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000473805; MAF= 0.04738%, 7/14774 alleles, homozygotes = 0); grpmax FAF= 0.00022756.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingRASopathy VCEP BP4 (Supporting) applies to splicing variants for which the predicted outcome is negligible. SpliceAI predicts no significant splice impact for NM_033360.4:c.-11-30T>C (max delta score = 0.01), well below any threshold for splice-altering prediction. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no donor/acceptor gain or loss predicted.
- VCEP BP4 rule: splicing predicted outcome is negligible.
Sources
BP7 SupportingRASopathy VCEP BP7 (Supporting) applies to intronic positions (excluding canonical splice sites) when splicing prediction algorithms predict no splice impact AND the nucleotide is not highly conserved. This variant resides in intron 1, SpliceAI predicts no splice impact (max delta = 0.01), and the variant is observed in gnomAD (8 alleles in v2.1, predominantly East Asian), consistent with a position that tolerates variation and is not under strong purifying selection. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no splice impact predicted.
- gnomAD v2.1: 8/213
- 854 alleles
- present in East Asian population (7/14
- 774).
- VCEP BP7 rule explicitly extends to intronic positions outside canonical splice sites.
Still missing
- Direct phyloP/GERP++ conservation scores not available
- nucleotide conservation inferred from gnomAD population variation data.
Sources
PP3 RASopathy VCEP PP3 requires REVEL ≥ 0.7 for missense variants OR a splicing prediction matching the disease mechanism for splicing variants. REVEL is unavailable (intronic variant). SpliceAI predicts no significant splice impact (max delta = 0.01); thus the computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no splice impact predicted.
- REVEL not applicable (intronic variant).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,561,408 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243114
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_033360.4%3Ac.-11-30T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25398359-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25245425-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-25245425-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_033360.4%3Ac.-11-…
- OncoKB ↗www.oncokb.org/gene/KRAS/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KRAS+c.-11-30T%3EC
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 7.04492e-06; MAF= 0.00070%, 11/1561408 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000188973; MAF= 0.01890%, 8/42334 alleles, homozygotes = 0); grpmax FAF= 9.393e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.74087e-05; MAF= 0.00374%, 8/213854 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000473805; MAF= 0.04738%, 7/14774 alleles, homozygotes = 0); grpmax FAF= 0.00022756.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).