NM_000077.5:c.183G>A

CDKN2A · NP_000068.1:p.(Glu61=) · NM_000077.5

GRCh37: chr9:21971175 C>T · GRCh38: chr9:21971176 C>T

Gene: CDKN2A Transcript: NM_000077.5

Final call

VUS

PM2_Moderate BP7_Supporting

Variant details

Gene

CDKN2A

Transcript

NM_000077.5

Protein

NP_000068.1:p.(Glu61=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The CDKN2A c.183G>A (p.Glu61=) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and observed at 0/1,596,036 alleles in gnomAD v4.1 (AF 0.00000%), which is below the 0.1% PM2 rarity threshold.

In silico data support a silent variant without splice effect: the protein consequence is p.(Glu61=), SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and REVEL is 0.083.

Final determination: The combination of PM2_Moderate and BP7_Supporting does not meet ACMG/AMP thresholds for pathogenic, likely pathogenic, likely benign, or benign classification; therefore the variant is classified as of uncertain significance.

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
PVS1	N/A	This variant is a synonymous change, p.(Glu61=), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants. Although CDKN2A loss of function is an established germline disease mechanism, available evidence does not support applying PVS1 to this specific variant.	pvs1_gene_context pvs1_variant_assessment prefetch
PS1	N/A	This variant does not alter the amino acid sequence and therefore does not meet the requirement for the same amino acid change as a previously established pathogenic variant.	prefetch clinvar
PS2	Not assessed	No confirmed de novo data with verified maternity and paternity were identified for this variant.	literature_pass
PS3	Not assessed	No well-established functional studies showing a damaging effect on CDKN2A function or splicing were identified for this variant.	literature_pass spliceai
PS4	Not assessed	No evidence was identified showing this variant is enriched in affected individuals compared with controls.	clinvar literature_pass
PM1	Not met	Available evidence does not support location in a mutational hotspot or other well-established critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and observed at 0/1,596,036 alleles in gnomAD v4.1 (AF 0.00000%), which is below the 0.1% rarity threshold and supports rarity in population databases.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder.	literature_pass
PM4	N/A	This variant is a synonymous substitution and does not change protein length or create an in-frame deletion or insertion.	prefetch
PM5	N/A	This criterion applies to a novel missense change at a residue with a different established pathogenic missense change. This variant is synonymous and does not create a missense substitution.	prefetch
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant.	literature_pass
PP1	Not assessed	No segregation data were identified to show that this variant tracks with disease in affected family members.	literature_pass
PP2	N/A	This criterion is intended for missense variants in genes where missense variation is a common disease mechanism. This variant is synonymous.	prefetch
PP3	N/A	This variant is synonymous and available computational data do not predict a deleterious effect. SpliceAI shows a maximum delta score of 0.00, arguing against a splice impact.	spliceai prefetch
PP4	Not assessed	No phenotype or family-history information was provided to determine whether the clinical presentation is highly specific for a CDKN2A-related disorder.
PP5	Not assessed	No reputable source classification supporting pathogenicity was identified for this variant.	clinvar
BA1	Not met	Population frequency does not meet the standalone benign threshold. In gnomAD v4.1 the allele frequency is 0.00000% (0/1,596,036 alleles), which is below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency does not exceed the strong benign threshold. In gnomAD v4.1 the allele frequency is 0.00000% (0/1,596,036 alleles), which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults at a frequency inconsistent with disease penetrance.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect were identified for this variant.	literature_pass
BS4	Not assessed	No family data were identified to show lack of segregation with disease.	literature_pass
BP1	N/A	This criterion applies to missense variants. This variant is synonymous.	prefetch
BP2	Not assessed	No phase data were identified to show this variant occurs in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.	literature_pass
BP3	N/A	This criterion applies to in-frame deletions or insertions in repetitive regions. This variant is a synonymous single-nucleotide substitution.	prefetch
BP4	N/A	For this synonymous variant, splice prediction is more appropriately considered under BP7 rather than BP4. Available computational data do not indicate a splice-disrupting effect.	spliceai prefetch
BP5	Not assessed	No evidence was identified that the reported phenotype is explained by an alternate molecular cause independent of this variant.
BP6	Not assessed	No reputable source classification supporting a benign interpretation was identified for this variant.	clinvar
BP7	Met	This variant is a synonymous substitution, p.(Glu61=), with no predicted effect on the protein sequence, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. These findings support a silent change without evidence of splice disruption.	prefetch spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.