Variant classification summary

NM_004985.4:c.24A>G

KRAS · NP_004976.2:p.(Val8=) · NM_004985.4

GRCh37: chr12:25398295 T>C · GRCh38: chr12:25245361 T>C

Gene: KRAS Transcript: NM_004985.4

Final call

Benign

BS1 strong BA1 stand-alone benign BP4 supporting BP6 supporting benign

Variant details

Gene

KRAS

Transcript

NM_004985.4

Protein

NP_004976.2:p.(Val8=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KRAS c.24A>G (p.Val8=) variant has been reported in ClinVar with an expert panel classification of likely benign, with additional benign and likely benign clinical laboratory submissions.

2

This variant is present in population databases at a frequency above the KRAS VCEP benign thresholds, with grpmax filtering allele frequencies of 0.0402% in gnomAD v2.1 and 0.056632% in gnomAD v4.1, exceeding the BS1 threshold of 0.025% and the BA1 threshold of 0.05% in v4.1.

3

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, supporting no expected clinically meaningful effect on splicing.

Final determination: Rule17 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
BP7	Not assessed	This synonymous variant has no predicted splice effect by SpliceAI (max delta score 0.02), but the KRAS VCEP rule for BP7 also requires that the altered nucleotide is not highly conserved, and no conservation evidence was identified here.	cspec spliceai
PM5	Not met	This variant is synonymous and does not create a novel amino acid substitution, so it does not meet the KRAS VCEP PM5 rule for a different missense change at the same codon.	cspec
BP5	Not assessed	No evidence was identified for an alternative molecular explanation of a RASopathy phenotype in another gene, so BP5 could not be evaluated.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be assessed.	cspec
BS1	Met	This variant is present in gnomAD above the KRAS VCEP BS1 threshold of 0.025% filtering allele frequency. The observed grpmax FAF is 0.0402% in gnomAD v2.1 and 0.056632% in gnomAD v4.1, both above the BS1 threshold.	cspec gnomad_v2 gnomad_v4
PP5	N/A	PP5 is not for use in this VCEP framework.	cspec
BP1	Not met	This variant is a synonymous substitution rather than a truncating loss-of-function variant, so it does not meet the KRAS VCEP BP1 rule.	cspec pvs1_variant_assessment
BP2	Not assessed	No phase data or evidence of another pathogenic RASopathy variant in the same gene were identified, so BP2 could not be assessed.	cspec
BA1	Met	This variant is present in gnomAD above the KRAS VCEP BA1 threshold of 0.05% filtering allele frequency. The gnomAD v4.1 grpmax FAF is 0.056632%, which is above the BA1 threshold.	cspec gnomad_v4
PS3	Not met	No approved variant-specific functional study was identified showing a damaging effect for this synonymous KRAS variant, so PS3 is not met.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM4	Not met	This variant does not alter protein length and is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 is not met.	cspec
BS3	N/A	BS3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PM1	Not met	Codon 8 is outside the KRAS VCEP PM1 domains P-loop (amino acids 10-17), Switch I (25-40), Switch II (57-64), and SAK (145-156), and no hotspot evidence was identified for this residue, so PM1 is not met.	cspec vcep_alignment_with_pm1_domains_pptx hotspots
BS2	Not assessed	Population frequency data alone do not establish observation in clinically evaluated unaffected individuals under the KRAS VCEP BS2 point-based framework, so BS2 was not assessed.	cspec gnomad_v2 gnomad_v4
PP2	N/A	PP2 is not applicable in this VCEP framework.	cspec
PM6	Not assessed	No assumed de novo report without confirmed parentage was identified for this variant, so PM6 could not be assessed.	cspec
BS4	Not assessed	No informative non-segregation data were identified for this variant, so BS4 could not be assessed.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity confirmation was identified for this variant, so PS2 could not be assessed.	cspec
PS4	Not met	No evidence was identified that this variant is enriched in individuals with a KRAS-related RASopathy, and no exact proband count meeting the KRAS VCEP point thresholds was found, so PS4 is not met.	cspec clinvar
PVS1	N/A	PVS1 is not applicable in the KRAS VCEP framework for this variant, and this synonymous change is not a null variant within the generic PVS1 categories.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	This variant does not change the amino acid sequence, so it does not meet PS1 for the same amino acid change as a previously established pathogenic variant.	cspec
PM3	N/A	PM3 is not applicable in the KRAS RASopathy VCEP framework.	cspec
PP4	N/A	PP4 is not applicable in this VCEP framework because phenotype-based evidence is handled through other RASopathy-specific criteria.	cspec
PM2	Not met	This variant is present in gnomAD and therefore does not meet the KRAS VCEP PM2 rule requiring absence from controls.	cspec gnomad_v2 gnomad_v4
BP4	Met	SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.02, which supports a negligible effect on splicing and meets BP4 at supporting strength.	cspec spliceai
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, and no REVEL, BayesDel, or HCI prior score was available for this synonymous variant.	cspec spliceai
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.	cspec clinvar

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