NM_024529.5:c.237+29_237+32del

CDC73 · NP_078805.3:p.? · NM_024529.5

GRCh37: chr1:193094368 TTATC>T · GRCh38: chr1:193125238 TTATC>T

Gene: CDC73 Transcript: NM_024529.5

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

CDC73

Transcript

NM_024529.5

Protein

NP_078805.3:p.?

gnomAD AF

0.04741445991958534 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant has an allele frequency of 7.99% in gnomAD v2.1 (22,520/281,690 alleles, 2,860 homozygotes) and 4.74% in gnomAD v4.1 (63,137/1,331,598 alleles, 5,691 homozygotes), with a highest subpopulation frequency of 49.26% in East Asians, far exceeding the BA1 stand-alone benign threshold of >1%.

The variant is observed in 2,860 homozygotes in gnomAD v2.1 and 5,691 homozygotes in gnomAD v4.1. CDC73 is associated with autosomal dominant hyperparathyroidism-jaw tumor syndrome with high penetrance; the presence of thousands of homozygous individuals in population databases is incompatible with pathogenicity (BS2).

SpliceAI predicts no splice impact (max delta score = 0.00), consistent with a benign intronic variant (BP4).

ClinVar reports this variant as Benign by two clinical laboratories using criteria-based assessment (BP6).

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 variant is an intronic deletion (c.237+29_237+32del, deep intronic, +29 to +32 of intron 2) and does not fall into the default generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). SpliceAI predicts no splice impact (max delta = 0.00). PVS1 cannot be applied to this variant.	pvs1_variant_assessment pvs1_gene_context spliceai
PS1	N/A	No pathogenic variant has been identified at the same nucleotide position with a different change. This criterion requires a same-site comparator variant with established pathogenicity.
PS2	N/A	No de novo data are available for this variant. PS2 requires a confirmed de novo observation in a patient with the disease and no family history.
PS3	N/A	No well-established in vitro or in vivo functional studies have been identified for this specific intronic variant. PS3 requires functional evidence supporting a damaging effect.
PS4	N/A	No case-control or cohort studies comparing variant prevalence in affected vs. unaffected individuals are available. The variant is observed at high frequency in population databases, making it unlikely to be enriched in affected populations.	gnomad_v2 gnomad_v4
PS5	N/A	This variant has not been classified as Pathogenic by an expert panel or reputable source. ClinVar reports it as Benign.	clinvar
PM1	N/A	This variant is located in intron 2 (c.237+29_237+32del), not in a known functional domain or mutational hotspot. No critical functional domain or established hotspot encompasses this deep intronic position.
PM2	Not met	This variant is present at high frequency in population databases: gnomAD v2.1 AF = 7.99% (22,520/281,690 alleles, 2,860 homozygotes) and gnomAD v4.1 AF = 4.74% (63,137/1,331,598 alleles, 5,691 homozygotes). PM2 requires absence or very low frequency in population databases.	gnomad_v2 gnomad_v4
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions causing protein length changes. This is an intronic deletion (c.237+29_237+32del) that does not alter the protein coding sequence.
PM5	N/A	This variant is an intronic deletion without a defined protein residue; no amino acid change is predicted (p.?). PM5 requires a same-residue missense comparator with established pathogenicity. Per pm5_candidates.json: eligible_for_classic_pm5_search = false.	pm5_candidates
PM6	N/A	No de novo observation has been reported for this variant. PM6 requires a confirmed de novo event with confirmed maternity and paternity.
PP1	N/A	No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	N/A	This variant is an intronic deletion, not a missense variant. PP2 applies specifically to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not available for this non-SNV variant. The computational evidence does not support pathogenicity.	spliceai
PP4	N/A	No patient phenotype or clinical data are available for this variant. PP4 requires that the variant is found in a patient whose phenotype or family history is highly specific for the disease.
PP5	N/A	ClinVar classifies this variant as Benign, not Pathogenic. PP5 requires a reputable source to have recently reported the variant as pathogenic.	clinvar
BA1	Met	This variant has an allele frequency of 7.99% in gnomAD v2.1 (22,520/281,690 alleles, 2,860 homozygotes) and 4.74% in gnomAD v4.1 (63,137/1,331,598 alleles, 5,691 homozygotes), with a highest subpopulation frequency of 49.26% in East Asians. These frequencies far exceed the BA1 threshold of >1%. The variant is a common population polymorphism.	gnomad_v2 gnomad_v4
BS1	Met	This variant has an allele frequency of 7.99% in gnomAD v2.1, exceeding the BS1 threshold of >0.3%. This evidence is superseded by BA1 (stand-alone benign).	gnomad_v2 gnomad_v4
BS2	Met	This variant is observed in 2,860 homozygotes in gnomAD v2.1 and 5,691 homozygotes in gnomAD v4.1. CDC73 is associated with autosomal dominant hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid carcinoma, disorders with high penetrance. The observation of thousands of apparently healthy homozygous adults is incompatible with a pathogenic role.	gnomad_v2 gnomad_v4 pvs1_gene_context
BS3	N/A	No well-established in vitro or in vivo functional studies have been performed on this specific variant demonstrating no damaging effect on protein function or splicing. BS3 requires functional evidence, not solely computational predictions.
BS4	N/A	No segregation data are available to assess lack of segregation with disease. BS4 requires non-segregation in affected family members.
BP1	N/A	This variant is an intronic deletion, not a missense variant. BP1 applies specifically to missense variants in genes where a truncating mechanism is the primary cause of disease.
BP2	N/A	No data are available on whether this variant has been observed in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	This variant is an intronic deletion, not an in-frame deletion/insertion in a repetitive region. BP3 applies to in-frame deletions/insertions in repetitive regions without known function.
BP4	Met	Multiple lines of computational evidence suggest no impact on splicing. SpliceAI predicts no splice impact (max delta score = 0.00) for this intronic deletion. No in silico predictors suggest a deleterious effect on gene or gene product.	spliceai
BP5	N/A	No data are available on whether this variant is found in cases with an alternate molecular basis for disease. BP5 requires observation in a case with a clear alternate genetic cause.
BP6	Met	ClinVar reports this variant as Benign by two clinical laboratories (GeneDx and Center for Genomic Medicine, Rigshospitalet). Both submissions used criteria-based assessment in a clinical testing context.	clinvar
BP7	N/A	This variant is an intronic deletion (c.237+29_237+32del), not a synonymous (silent) variant. BP7 applies specifically to synonymous variants with no predicted splice impact. While the variant has no predicted splice impact (SpliceAI delta = 0.00), the strict definition of BP7 requires a synonymous coding change.	spliceai

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