Variant classification summary

NM_053056.3:c.723G>A

CCND1 · NP_444284.1:p.(Pro241=) · NM_053056.3

GRCh37: chr11:69462910 G>A · GRCh38: chr11:69648142 G>A

Gene: CCND1 Transcript: NM_053056.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

CCND1

Transcript

NM_053056.3

Protein

NP_444284.1:p.(Pro241=)

gnomAD AF

0.4440231891532686 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_053056.3:c.723G>A (p.Pro241=) is a synonymous variant in CCND1 with an allele frequency of 44.66% in gnomAD v2.1 (125,943/282,012 alleles, 29,329 homozygotes) and 44.40% in gnomAD v4.1, meeting BA1 (stand-alone benign).

2

The variant has been observed in 29,329 homozygous individuals in gnomAD v2.1, demonstrating compatibility with normal health and meeting BS2.

3

ClinVar classifies this variant as Benign (Variation ID 13755, 2 clinical laboratories), meeting BP6.

4

SpliceAI predicts no splicing impact (max delta = 0.02) and the variant is synonymous (p.Pro241=), meeting BP7 and BP4.

5

No publications identified in the case materials mention NM_053056.3:c.723G>A specifically; papers cited by ClinVar submissions discuss the CCND1 c.870G>A polymorphism which is a different variant.

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	Synonymous variant (NP_444284.1:p.(Pro241=)) does not fall into any null-variant bucket. pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	Synonymous variant produces no amino acid change; there is no same-amino-acid pathogenic comparator possible.
PS2	Not assessed	No de novo data available for this variant.
PS3	Not met	No functional studies of NM_053056.3:c.723G>A or a systematically characterized range that includes this position were identified in the literature. The variant is synonymous and produces no amino acid change.
PS4	Not met	With an allele frequency of 44.6% in the general population (gnomAD), this variant is incompatible with enrichment in affected individuals for any rare Mendelian disease. No case-control studies demonstrating significant enrichment were identified.	gnomad_v2 gnomad_v4
PS5	Not assessed	No independent data identifying this variant as pathogenic from a source not already reviewed.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org negative). Although located in exon 4 of CCND1, the variant is synonymous (p.Pro241=) and does not alter the cyclin D1 protein; no domain-level pathogenic evidence applies.
PM2	Not met	This variant is extremely common in gnomAD: AF = 44.66% in v2.1 (125,943/282,012 alleles, 29,329 homozygotes) and 44.40% in v4.1 (716,284/1,613,168 alleles, 162,210 homozygotes). Far exceeds the PM2 threshold of <0.1% allele frequency.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant (p.Pro241=) with no alternative missense change at this residue. pm5_candidates.json confirms: unable to confirm classic same-residue PM5 semantics.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant.
PP1	Not assessed	No segregation data available for this variant.
PP2	N/A	This is a synonymous variant, not a missense variant. PP2 specifically applies to missense variants in genes where missense variants are a known mechanism and benign missense variation is rare.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI max delta = 0.02 predicts no splicing impact. REVEL and BayesDel scores are unavailable for this synonymous variant, consistent with absence of predicted amino acid effect.	spliceai
PP4	Not assessed	No patient phenotype or clinical data available for assessment.
PP5	Not met	ClinVar reports this variant as Benign (Variation ID 13755), not Pathogenic. PP5 requires a reputable source to report the variant as pathogenic; the ClinVar classification is the opposite.	clinvar
BA1	Met	Allele frequency far exceeds the 1% BA1 threshold: 44.66% in gnomAD v2.1 (125,943/282,012 alleles, 29,329 homozygotes) and 44.40% in gnomAD v4.1 (716,284/1,613,168 alleles, 162,210 homozygotes). This is a common polymorphism present in all populations, with highest frequency in East Asians (56.69% in v2.1).	gnomad_v2 gnomad_v4
BS1	Met	Allele frequency exceeds the 0.3% BS1 threshold. Superseded by BA1 for classification purposes but independently meets BS1 criteria.	gnomad_v2 gnomad_v4
BS2	Met	Observed in 29,329 homozygous individuals in gnomAD v2.1 and 162,210 homozygous individuals in gnomAD v4.1. This high number of healthy adult homozygotes demonstrates compatibility with normal development and excludes pathogenicity for any early-onset, fully penetrant Mendelian disorder.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this specific variant. The variant is synonymous with no predicted splice impact, but no dedicated functional studies were identified.
BS4	Not assessed	No segregation data available to assess lack of cosegregation with disease.
BP1	N/A	This is a synonymous variant, not a missense variant. BP1 specifically applies to missense variants in genes where primarily truncating variants are known to cause disease.
BP2	Not assessed	No data available on observations in trans with a known pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI max delta = 0.02 predicts no splicing effect. The variant is synonymous (p.Pro241=) and does not alter the amino acid sequence. REVEL and BayesDel scores are unavailable, as expected for a synonymous variant with no amino acid change.	spliceai
BP5	Not assessed	No data available. BP5 requires a case where an alternative molecular basis for disease was identified, excluding this variant.
BP6	Met	ClinVar reports this variant as Benign (Variation ID 13755) with review status 'criteria provided, single submitter,' from 2 clinical laboratories. A reputable source classifies this variant as benign.	clinvar
BP7	Met	Synonymous variant (p.Pro241=) at a nucleotide position where SpliceAI predicts no splicing impact (max delta = 0.02). The variant does not alter the amino acid sequence and is not predicted to affect splicing, meeting BP7 criteria.	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.