Variant classification summary

NM_006265.2:c.165A>G

RAD21 · NP_006256.1:p.(Thr55=) · NM_006265.2

GRCh37: chr8:117875478 T>C · GRCh38: chr8:116863239 T>C

Gene: RAD21 Transcript: NM_006265.2

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

RAD21

Transcript

NM_006265.2

Protein

NP_006256.1:p.(Thr55=)

gnomAD AF

1.613279524256278e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 0.000016 (26/1,611,624 alleles), no homozygotes.

2

BP4 (Supporting): SpliceAI max delta 0.003, well below the ~0.2 splice-impact threshold.

3

BP7 (Supporting): synonymous change (p.(Thr55=)) with no predicted splice impact - all SpliceAI scores below 0.01.

4

Overall Likely Benign: two supporting benign criteria (BP4 + BP7) satisfy the '2 BP -> Likely Benign' rule.

Final determination: Generic ACMG/AMP 2015 fallback: two supporting-strength benign criteria (BP4, BP7) satisfy the '2 BP -> Likely Benign' combination rule.

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	Not applicable: this synonymous change yields the same amino acid (p.(Thr55=)), so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: the variant is synonymous (p.(Thr55=)) with no amino acid change to compare against known pathogenic missense variants.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo occurrence with confirmed maternity and paternity was documented.
PS3	Not assessed	Not assessed: no functional or splicing assay results for this variant were available.
PS4	Not assessed	Not assessed: no case-control enrichment or affected-case data for this exact variant were available.
PM1	N/A	Not applicable: synonymous change (p.(Thr55=)) leaves no altered residue to assess for hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 0.000016 (26/1,611,624 alleles), with no homozygotes.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no second pathogenic allele or phase evidence showing the variant in trans was available.
PM4	N/A	Not applicable: synonymous change causes no protein length alteration, so there is nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare with a previously pathogenic missense at the same position.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing or clinical documentation supporting a presumed de novo occurrence.
PP1	Not assessed	Not assessed: no co-segregation or pedigree data in relatives were documented.
PP2	N/A	Not applicable: this gene-constraint criterion applies to missense variants, and this change is synonymous.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta score 0.003, far below the ~0.2 threshold for a predicted splice effect.	spliceai
PP4	Not assessed	Not assessed: no patient-level phenotype was available to establish a highly specific phenotype-genotype match.
PP5	Not assessed	Not assessed: no ClinVar expert-panel Pathogenic or Likely pathogenic classification exists for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 0.000016, far below the >1% stand-alone benign population threshold.	gnomad_v4 gnomad_v2
BS1	Not assessed	Not assessed: no RAD21-specific expected allele-frequency threshold was available to test against.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no healthy adults homozygous for or carrying the expected disease genotype were documented.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence demonstrating a lack of damaging effect was available.
BS4	Not assessed	Not assessed: no unaffected carriers or non-segregation family data were reported.
BP1	N/A	Not applicable: this criterion addresses missense variants, and the change is synonymous (p.(Thr55=)).	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no evidence of this variant occurring with a pathogenic variant in cis or trans.
BP3	N/A	Not applicable: the variant is synonymous, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta score 0.003, well below the ~0.2 threshold for a predicted splice effect.	spliceai
BP5	Not assessed	Not assessed: no alternate molecular basis for the reported phenotype was documented.
BP6	Not assessed	Not assessed: no ClinVar expert-panel Benign or Likely benign classification exists for this exact variant.	clinvar
BP7	Met	Met (supporting): synonymous variant with no predicted splice impact - SpliceAI max delta 0.003, all four scores below 0.01.	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.