Classification rationale

PM2 BP4BP7 Likely Benign

RAD21 c.165A>G synonymous · exon 3

PM2 (Supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 0.000016 (26/1,611,624 alleles), no homozygotes. BP4 (Supporting): SpliceAI max delta 0.003, well below the ~0.2 splice-impact threshold. BP7 (Supporting): synonymous change (p.(Thr55=)) with no predicted splice impact - all SpliceAI scores below 0.01. Overall Likely Benign: two supporting benign criteria (BP4 + BP7) satisfy the '2 BP -> Likely Benign' rule.

PM2 + BP4 + BP7 → Likely Benign

Gene diagram · NM_006265.2 · variants mapped to exon structure

RAD21 NM_006265.2

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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

gnomAD v4.1: 26/1,611,624 alleles, AF 1.61328e-05, group-max FAF 1.456e-05, 0 homozygotes.gnomAD v2.1: 1/251,066 alleles, AF 3.98302e-06, 0 homozygotes.gnomAD-Canada v1.0: absent.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta score 0.003, well below the ~0.2 threshold for a predicted splice effect.

SpliceAI max delta score = 0.003 across all four splice-altering categories (acceptor gain/loss, donor gain/loss), indicating no predicted splicing disruption.

spliceai ↗

✓

BP7 supporting Benign

Met (supporting): synonymous variant with no predicted splice impact - SpliceAI max delta 0.003, all four scores below 0.01.

Variant is synonymous, NP_006256.1:p.(Thr55=), per normalization data in case_summary.json.SpliceAI predicts no significant splice impact for this variant (max delta score = 0.003).

spliceai ↗

Assessed · not applied · 2 not met · 15 not assessed

Pathogenic

PS2 Not assessed: no de novo occurrence with confirmed maternity and paternity was documented.

PS3 Not assessed: no functional or splicing assay results for this variant were available.

PS4 Not assessed: no case-control enrichment or affected-case data for this exact variant were available.

PM3 Not assessed: no second pathogenic allele or phase evidence showing the variant in trans was available.

PM6 Not assessed: no parental testing or clinical documentation supporting a presumed de novo occurrence.

PP1 Not assessed: no co-segregation or pedigree data in relatives were documented.

PP3 Not met: SpliceAI max delta score 0.003, far below the ~0.2 threshold for a predicted splice effect.

PP4 Not assessed: no patient-level phenotype was available to establish a highly specific phenotype-genotype match.

PP5 Not assessed: no ClinVar expert-panel Pathogenic or Likely pathogenic classification exists for this exact variant.

Benign

BA1 Not met: gnomAD v4.1 allele frequency 0.000016, far below the >1% stand-alone benign population threshold.

BS1 Not assessed: no RAD21-specific expected allele-frequency threshold was available to test against.

BS2 Not assessed: no healthy adults homozygous for or carrying the expected disease genotype were documented.

BS3 Not assessed: no functional assay evidence demonstrating a lack of damaging effect was available.

BS4 Not assessed: no unaffected carriers or non-segregation family data were reported.

BP2 Not assessed: no evidence of this variant occurring with a pathogenic variant in cis or trans.

BP5 Not assessed: no alternate molecular basis for the reported phenotype was documented.

BP6 Not assessed: no ClinVar expert-panel Benign or Likely benign classification exists for this exact variant.

N/A · 8 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.61328e-05; MAF= 0.00161%, 26/1611624 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.12185e-05; MAF= 0.00212%, 25/1178218 alleles, homozygotes = 0); grpmax FAF= 1.456e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.98302e-06; MAF= 0.00040%, 1/251066 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163292; MAF= 0.01633%, 1/6124 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0016% · 26 / 1,611,624
0 hom · FAF 0.0015%

European (non-Finnish) 25 / 1,178,218	0.0021%
Remaining individuals 1 / 62,372	0.0016%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,066
0 hom

Remaining individuals

1 / 6,124

0.016%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 2723729)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

20301283 ↗ Cornelia de Lange Syndrome. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR