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).1 The variant has been observed in 29,329 homozygous individuals in gnomAD v2.1, demonstrating compatibility with normal health and meeting BS2.2 ClinVar classifies this variant as Benign (Variation ID 13755, 2 clinical laboratories), meeting BP6.3 SpliceAI predicts no splicing impact (max delta = 0.02) and the variant is synonymous (p.Pro241=), meeting BP7 and BP4.4 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.
CCND1
Final classification
Benign
CCND1 c.723G>A · p.Pro241=
CCND1
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).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BS2 strong benign, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 stand-alone benign + 2 strong benign + 3 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BS2BP4BP6BP7
Benign
CCND1 c.723G>A
BA1 + BS1 + BS2 + BP4 + BP6 + BP7
→
Benign
Gene diagram
· NM_053056.3 · variants mapped to exon structure
CCND1
NM_053056.3
Fetching transcript structure from UCSC…
Applied criteria · 6 applied · 14 assessed
Applied · 6
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
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 v2.1 AF=44.66% (125943/282012 alleles
✓
BS1
strong
Benign
Allele frequency exceeds the 0.3% BS1 threshold. Superseded by BA1 for classification purposes but independently meets BS1 criteria.
gnomAD AF = 44.66% (v2.1)44.40% (v4.1)well above BS1 threshold of >0.3%.
✓
BS2
strong
Benign
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.
29329 homozygotes in gnomAD v2.1162
✓
BP4
supporting
Benign
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 max delta score = 0.02 (no predicted splicing impact)synonymous variant (p.Pro241=) with no amino acid change.
✓
BP6
supporting
Benign
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: Benign classification (Variation ID 13755)2 clinical laboratoriesreview status: criteria provided
✓
BP7
supporting
Benign
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.
Synonymous substitution p.Pro241= with no amino acid changeSpliceAI max delta = 0.02 (no splicing impact predicted).
Assessed · not applied
Pathogenic
PS2
No de novo data available for this variant.
PS3
No functional studies of NM_053056.3:c.723G>A or a systematically characterized range that includes this position were identified in the literature.
PS4
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.
PM1
This variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org negative).
PM2
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).
PM6
No de novo data available for this variant.
PP1
No segregation data available for this variant.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype or clinical data available for assessment.
PP5
ClinVar reports this variant as Benign (Variation ID 13755), not Pathogenic.
Benign
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this specific variant.
BS4
No segregation data available to assess lack of cosegregation with disease.
BP2
No data available on observations in trans with a known pathogenic variant.
BP5
No data available.
N/A · 5
PVS1 · PS1 · PM5 · PP2 · BP1
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.444023; MAF= 44.40232%, 716284/1613168 alleles, homozygotes = 162210) and has highest observed frequency in the East Asian population (AF= 0.525575; MAF= 52.55753%, 23571/44848 alleles, homozygotes = 6204); grpmax FAF= 0.519956.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.446587; MAF= 44.65874%, 125943/282012 alleles, homozygotes = 29329) and has highest observed frequency in the East Asian population (AF= 0.566911; MAF= 56.69110%, 11294/19922 alleles, homozygotes = 3160); grpmax FAF= 0.559639.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.4660823170731707, 8561/18368 alleles, homozygotes = 2065).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
44%
· 716284 / 1,613,168
162210 hom · FAF 52%
162210 hom · FAF 52%
East Asian 23571 / 44,848 |
53% 6204 hom |
South Asian 47620 / 91,060 |
52% 12712 hom |
Middle Eastern 3108 / 6,058 |
51% 824 hom |
European (Finnish) 30437 / 63,546 |
48% 7327 hom |
Remaining individuals 28397 / 62,486 |
45% 6540 hom |
European (non-Finnish) 530242 / 1,179,672 |
45% 119379 hom |
Ashkenazi Jewish 13148 / 29,600 |
44% 2908 hom |
Amish 360 / 912 |
39% 68 hom |
Admixed American 23115 / 59,992 |
39% 4492 hom |
African/African American 16286 / 74,994 |
22% 1756 hom |
gnomAD v2.1
45%
· 125943 / 282,012
29329 hom · FAF 56%
29329 hom · FAF 56%
East Asian 11294 / 19,922 |
57% 3160 hom |
South Asian 15976 / 30,590 |
52% 4244 hom |
European (Finnish) 12189 / 25,070 |
49% 3030 hom |
European (non-Finnish) 59874 / 128,642 |
47% 13989 hom |
Remaining individuals 3328 / 7,198 |
46% 807 hom |
Ashkenazi Jewish 4635 / 10,328 |
45% 1034 hom |
Admixed American 13309 / 35,362 |
38% 2483 hom |
African/African American 5338 / 24,900 |
21% 582 hom |
gnomAD Canada 🇨🇦
47%
· 8561 / 18,368
2065 hom · FAF 54%
2065 hom · FAF 54%
indel · split
East Asian 766 / 1,336 |
57% 227 hom |
Middle Eastern 80 / 144 |
56% 20 hom |
South Asian 691 / 1,362 |
51% 185 hom |
Remaining individuals 569 / 1,132 |
50% 144 hom |
European (Finnish) 4 / 8 |
50% 1 hom |
Ashkenazi Jewish 395 / 832 |
47% 88 hom |
European (non-Finnish) 5495 / 11,700 |
47% 1313 hom |
Latino/Admixed American 324 / 836 |
39% 66 hom |
African/African American 237 / 1,018 |
23% 21 hom |
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories). (ClinVarID = 13755)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57118864, n = 79 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
10667569 ↗
Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer.
CLINVAR
12097293 ↗
Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease.
CLINVAR
24870244 ↗
Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
23502783 ↗
The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma.
CLINVAR