Variant classification summary

NM_024529.5:c.424-28A>G

CDC73 · NP_078805.3:p.? · NM_024529.5

GRCh37: chr1:193107187 A>G · GRCh38: chr1:193138057 A>G

Gene: CDC73 Transcript: NM_024529.5

Final call

Benign

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

Variant details

Gene

CDC73

Transcript

NM_024529.5

Protein

NP_078805.3:p.?

gnomAD AF

0.009931653559399307 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

This variant has been observed in population databases at an allele frequency exceeding the BA1 threshold: gnomAD v2.1 grpmax FAF 1.056% (Ashkenazi Jewish AF 1.32%, 10 homozygotes) and gnomAD v4.1 grpmax FAF 1.147% (Ashkenazi Jewish AF 1.39%, 102 homozygotes). This frequency and the presence of homozygotes is incompatible with a highly penetrant dominant disorder. BA1 (stand-alone benign) is met.

2

This variant is present in gnomAD at an allele frequency exceeding the BS1 threshold: gnomAD v2.1 overall AF 0.76% and gnomAD v4.1 overall AF 0.99%, both well above 0.3%. BS1 (strong benign) is met.

3

SpliceAI predicts no significant splice impact for this intronic variant (max delta score 0.07). No in silico evidence supports a deleterious effect. BP4 (supporting benign) is met.

4

This variant has been reported in ClinVar as Benign by a clinical laboratory (SCV002760434, Center for Genomic Medicine, Rigshospitalet) with criteria provided. BP6 (supporting benign) is met.

5

No pathogenic criteria are met. The variant is an intronic substitution (c.424-28A>G) with no splice impact, absent from COSMIC, and has no functional or segregation data supporting pathogenicity.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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 is an intronic variant (c.424-28A>G, intron 5) with SpliceAI max delta 0.07, indicating no significant splice impact. Does not meet null variant criteria (nonsense, frameshift, or canonical ±1,2 splice consensus).	pvs1_generic_framework spliceai
PS1	N/A	Not a missense variant; intronic change cannot be compared to a known pathogenic missense change at the same amino acid position.
PS2	Not assessed	No de novo data available for this variant.
PS3	Not met	No functional data available for NM_024529.5:c.424-28A>G. No experimental studies testing this variant or a systematically characterized range that includes it were identified.
PS4	Not met	No case-control or cohort data demonstrating enrichment of this variant in affected individuals compared to controls.
PS5	N/A	PS5 requires an established pathogenic variant from a reputable source. This intronic variant has no functional consequence and no established pathogenicity mechanism; not a de novo candidate for this criterion.
PM1	N/A	Intronic variant at -28 position in intron 5 with SpliceAI max delta 0.07, indicating no significant splice impact. Not located in a mutational hot spot or critical functional domain.	spliceai
PM2	Not met	This variant is present in gnomAD v2.1 at 0.76% (2161/282588 alleles, 10 homozygotes) and in gnomAD v4.1 at 0.99% (15162/1526634 alleles, 102 homozygotes), well above the 0.1% PM2 threshold for absence from population databases.	gnomad_v2 gnomad_v4
PM5	N/A	Intronic variant has no amino acid residue context; PM5 requires a same-residue missense comparator. No candidates identified in ClinVar.
PM6	Not assessed	No de novo data available for this variant.
PP1	Not assessed	No segregation data available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is an intronic variant.
PP3	Not met	SpliceAI max delta score is 0.07, which does not support a deleterious splicing effect. No other in silico scores are available (REVEL and BayesDel are not applicable to intronic variants).	spliceai
PP4	Not assessed	No patient phenotype or clinical data available for this case.
PP5	Not met	ClinVar classifies this variant as Benign, not Pathogenic. PP5 requires a pathogenic classification from a reputable source. The single ClinVar submission (SCV002760434, Center for Genomic Medicine, Rigshospitalet) reports Benign.	clinvar
BA1	Met	This variant has a maximum population allele frequency exceeding 1%. gnomAD v2.1 grpmax FAF is 1.056% (Ashkenazi Jewish AF=1.32%) and gnomAD v4.1 grpmax FAF is 1.147% (Ashkenazi Jewish AF=1.39%). Additionally, 10 homozygotes are observed in gnomAD v2.1 and 102 homozygotes in gnomAD v4.1, incompatible with a highly penetrant dominant disorder.	gnomad_v2 gnomad_v4
BS1	Met	This variant is present in gnomAD at an allele frequency well above 0.3%. gnomAD v2.1 overall AF is 0.76% (2161/282588 alleles) and gnomAD v4.1 overall AF is 0.99% (15162/1526634 alleles), both exceeding the BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No specific observation in healthy adult controls documented for this variant in the context of full penetrance expected at early age. While the variant has many gnomAD homozygotes, BS2 requires documented observation in healthy adults for a disorder expected to be fully penetrant at an early age, which is better captured by BA1 population frequency data.
BS3	Not met	No functional data demonstrating no damaging effect for this variant. SpliceAI max delta 0.07 does not constitute a functional assay showing no protein effect — it is in silico prediction, addressable under BP4/BP7.
BS4	Not assessed	No segregation data available for non-segregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where a truncating mechanism is primary. This is an intronic variant, not a missense change.
BP2	Not assessed	No data on observation in trans with a pathogenic variant for a fully penetrant dominant disorder. The 10 homozygotes in gnomAD are addressed under BA1.
BP4	Met	SpliceAI predicts no significant splice impact (max delta score = 0.07). Multiple lines of in silico evidence (absence of splice-altering prediction, no REVEL/BayesDel scores for intronic variant) support a benign interpretation.	spliceai
BP5	Not assessed	No case data available for an alternative molecular basis of disease.
BP6	Met	This variant has been reported in ClinVar as Benign by a clinical laboratory (Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital; SCV002760434) with criteria provided. While this is a single submitter (1-star), the classification is Benign with documented criteria.	clinvar
BP7	N/A	BP7 applies to synonymous variants at non-conserved nucleotides with no predicted splice impact. This is an intronic substitution, not a synonymous coding variant.

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