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CYP21A2c.1439Likely benign
Print report
Variant interpretation report

CYP21A2 c.1439

NM_000500.9:c.1439 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About CYP21A2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BS1Supporting
BS1 · supporting

BS1 applies when allele frequency is >0.3% in a general population database for a recessive disorder. The variant was observed in 1 of 92 healthy Hungarian blood donors (1.09%) by Blasko et al. 2009 (PMID:19505723), a healthy population cohort. Although gnomAD data are unavailable, this observation in an unselected healthy population at >0.3% supports benign classification. Note: sample size is limited (n=92), warranting caution.

BS3Supporting
BS3 · supporting

Well-established in vitro functional studies by Robins et al. 2007 (PMID:17119906) demonstrate that the R479L (p.Arg480Leu) mutant retains 75.5% activity toward 17-hydroxyprogesterone and 79.6% activity toward progesterone compared to wild-type enzyme, with normal substrate binding kinetics (Km and Vmax not significantly different). Protein expression was confirmed by Western blot to be comparable to wild-type. This near-normal enzymatic activity in a well-validated assay using both natural substrates indicates no damaging effect on protein function, supporting a benign interpretation.

BP6Supporting
BP6 · supporting

BP6 applies when a reputable source (e.g., clinical diagnostic laboratory) has recently reported the variant as benign. In ClinVar (variation ID 445854), NM_000500.9:c.1439G>T has been classified as Benign by three clinical diagnostic laboratories (Center for Pediatric Genomic Medicine, Mendelics, GeneDx) and as Likely benign by three additional clinical laboratories (Quest Diagnostics, Athena Diagnostics, and one other submitter). Multiple independent clinical laboratories have reached a benign or likely benign conclusion, supporting BP6 at the supporting level.

Recorded classification: Likely 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: BS1 supporting, BS3 supporting, BP6 supporting; combination = 3 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
8 reported laboratory submissions

3 Benign · 2 Uncertain significance · 1 Likely benign · 1 likely benign · 1 Likely Benign.

Applied · BP6 → ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

Applied · BS3 → OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 17 not met · 2 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

Functional studies in transiently transfected mammalian cells demonstrate the p.Arg480Leu (R479L) mutant retains 75.5% activity toward 17-hydroxyprogesterone and 79.6% activity toward progesterone compared to wild-type, with normal substrate binding kinetics.

The variant has been observed in a healthy population cohort at a frequency exceeding the benign threshold for a recessive disorder, with 1 heterozygote identified among 92 healthy Hungarian blood donors (1.09%).

Multiple independent clinical diagnostic laboratories have classified this variant as Benign (three laboratories) or Likely benign (three laboratories) in ClinVar (variation ID 445854).

The variant is also present in affected populations at a comparable low frequency (2/250 alleles, 0.8%, in a Sicilian CAH cohort), consistent with a benign polymorphism rather than a disease-causing allele.

No pathogenic or likely pathogenic classifications for this variant have been reported by any clinical laboratory or expert panel.

Met · 3

BS1 SupportingBS1 applies when allele frequency is >0.3% in a general population database for a recessive disorder. The variant was observed in 1 of 92 healthy Hungarian blood donors (1.09%) by Blasko et al. 2009 (PMID:19505723), a healthy population cohort. Although gnomAD data are unavailable, this observation in an unselected healthy population at >0.3% supports benign classification. Note: sample size is limited (n=92), warranting caution. Details ▾Hide ▴
Evidence considered
  • Observed in 1/92 (1.09%) healthy Hungarian blood donors.
Still missing
  • Small sample size (n=92)
  • gnomAD v2.1 and v4.1 data unavailable for independent confirmation.
Sources
PMID:19505723 ↗19505723
BS3 SupportingWell-established in vitro functional studies by Robins et al. 2007 (PMID:17119906) demonstrate that the R479L (p.Arg480Leu) mutant retains 75.5% activity toward 17-hydroxyprogesterone and 79.6% activity toward progesterone compared to wild-type enzyme, with normal substrate binding kinetics (Km and Vmax not significantly different). Protein expression was confirmed by Western blot to be comparable to wild-type. This near-normal enzymatic activity in a well-validated assay using both natural substrates indicates no damaging effect on protein function, supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
  • In vitro functional assay: 75.5% residual activity (17OHP)
  • 79.6% (progesterone)
  • Km and Vmax normal
  • protein expression confirmed by Western blot.
Sources
PMID:17119906 ↗17119906
BP6 SupportingBP6 applies when a reputable source (e.g., clinical diagnostic laboratory) has recently reported the variant as benign. In ClinVar (variation ID 445854), NM_000500.9:c.1439G>T has been classified as Benign by three clinical diagnostic laboratories (Center for Pediatric Genomic Medicine, Mendelics, GeneDx) and as Likely benign by three additional clinical laboratories (Quest Diagnostics, Athena Diagnostics, and one other submitter). Multiple independent clinical laboratories have reached a benign or likely benign conclusion, supporting BP6 at the supporting level. Details ▾Hide ▴
Evidence considered
  • ClinVar: 3 clinical laboratories classify as Benign
  • 3 classify as Likely benign (variation ID 445854).
Sources
clinvar ↗

Not met · 17 · evaluated, threshold not reached

PS2 No evidence of a de novo occurrence of NM_000500.9:c.1439G>T with confirmed maternity and paternity has been reported. CYP21A2 mutations are typically inherited in an autosomal recessive pattern, and de novo occurrences are rare. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in reviewed literature.
Sources
1511032016788163171199061950572321169732
PS3 Functional studies by Robins et al. 2007 (PMID:17119906) demonstrated that the R479L (p.Arg480Leu) mutant retains 75.5% activity toward 17-hydroxyprogesterone and 79.6% activity toward progesterone relative to wild-type, with normal substrate binding kinetics. This near-normal enzyme activity does not support a damaging effect and therefore does not meet PS3. Details ▾Hide ▴
Evidence considered
  • In vitro functional assay: 75.5% activity (17OHP)
  • 79.6% activity (progesterone) vs wild-type. Km and Vmax not significantly different from wild-type.
Sources
PMID:17119906 ↗17119906
PS4 The variant has been observed in both affected and healthy populations. It was detected in 2 of 250 CYP21A2 alleles (0.8%) in a Sicilian CAH cohort (PMID:21169732) and in 1 of 92 healthy Hungarian blood donors (PMID:19505723). The similar prevalence in affected and general populations does not support statistically significant enrichment in cases versus controls. Details ▾Hide ▴
Evidence considered
  • 2/250 alleles (0.8%) in CAH cohort
  • 1/92 (1.09%) in healthy controls.
Still missing
  • Larger case-control studies would be needed to establish PS4.
Sources
PMID:21169732 ↗PMID:19505723 ↗2116973219505723
PM1 PM1 applies to variants located in a mutational hot spot or well-established critical functional domain without benign variation. Structural modeling by Robins et al. 2006 (PMID:16788163) places residue Arg479 (Arg480 in NM numbering) in a surface-exposed loop region, not in the heme-binding pocket, steroid-binding site, or redox partner interaction interface. This residue is not part of a recognized critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • Residue Arg480 located in surface-exposed loop
  • not in critical functional domain (heme/steroid-binding or redox partner interface).
Sources
PMID:16788163 ↗16788163
PM2 PM2 requires the variant to be absent from or at extremely low frequency (<0.1%) in population databases. The variant was observed in 1 of 92 healthy Hungarian individuals (1.09%) by Blasko et al. 2009 (PMID:19505723). gnomAD v2.1 and v4.1 data are unavailable for this variant. The observation of the variant in a healthy population at >0.1% precludes application of PM2. Details ▾Hide ▴
Evidence considered
  • Observed in 1/92 healthy individuals (1.09%)
  • gnomAD data unavailable.
Still missing
  • gnomAD v2.1 and v4.1 frequency data could not be retrieved.
Sources
PMID:19505723 ↗19505723
PM6 No evidence of a de novo occurrence of NM_000500.9:c.1439G>T without confirmation of maternity and paternity has been identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Sources
1511032016788163171199061950572321169732
PP1 No co-segregation data for NM_000500.9:c.1439G>T in multiple affected family members has been reported. The R479L carrier in Robins et al. 2007 (PMID:17119906) was heterozygous with wild-type on the other allele and lacked affected family members for segregation analysis. Details ▾Hide ▴
Evidence considered
  • Single heterozygous carrier reported
  • no co-segregation data in affected families.
Sources
17119906
PP2 PP2 requires the gene to have a low rate of benign missense variation with missense variants as a common disease mechanism. CYP21A2 has multiple well-characterized benign missense variants (e.g., p.Leu9del, p.Arg102Lys, p.Asn493Ser) occurring at appreciable population frequencies, indicating a high rate of benign missense variation. Therefore PP2 is not met. Details ▾Hide ▴
Evidence considered
  • CYP21A2 has frequent benign missense polymorphisms: +L9 (MAF ~37%)
  • R102K (~34%)
  • N493S (~28%).
Sources
PMID:19505723 ↗19505723
PP3 Multiple lines of computational evidence are required for PP3. REVEL, BayesDel, and SpliceAI scores are unavailable for this variant (mutalyzer normalization did not produce the required genomic coordinates). Without in silico predictions, PP3 cannot be assessed as met. Details ▾Hide ▴
Evidence considered
  • REVEL and BayesDel scores unavailable
  • SpliceAI max delta unavailable.
Still missing
  • In silico prediction tools could not be queried
  • variant normalization to genomic coordinates was unsuccessful.
PP4 PP4 requires the patient's phenotype or family history to be highly specific for the disease. No patient-specific clinical data for NM_000500.9:c.1439G>T carriers with highly specific phenotype was available for adjudication. Details ▾Hide ▴
Evidence considered
  • No patient-specific phenotype data available for adjudication.
PP5 PP5 requires a reputable source to have recently reported the variant as pathogenic. In ClinVar (ID 445854), the variant is classified as Benign by 3 clinical laboratories, Likely benign by 3 clinical laboratories, and Uncertain significance by 2 clinical laboratories. No clinical laboratory or expert panel has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: Benign (3 labs)
  • Likely benign (3 labs)
  • VUS (2 labs)
  • no pathogenic classifications.
Sources
clinvar ↗
BA1 BA1 requires allele frequency >1% in a general population database. gnomAD v2.1 and v4.1 data are unavailable. The variant was observed at 1.09% (1/92) in a small healthy Hungarian cohort (PMID:19505723), but this single small study does not meet the rigorous population database standard required for BA1. Details ▾Hide ▴
Evidence considered
  • Observed in 1/92 healthy Hungarians (1.09%)
  • gnomAD data unavailable.
Still missing
  • gnomAD population frequency data could not be retrieved to confirm >1% frequency.
Sources
PMID:19505723 ↗19505723
BS2 BS2 requires observation of the variant in a healthy adult individual when full penetrance is expected at an early age, either in trans with a known pathogenic variant (for recessive disorders) or in the homozygous state. No such observation has been reported for NM_000500.9:c.1439G>T. Details ▾Hide ▴
Evidence considered
  • No observation in trans with pathogenic variant in unaffected individual or in homozygous state in healthy adult.
Sources
1711990619505723
BS4 BS4 requires lack of segregation of the variant with disease in affected family members. No segregation data for NM_000500.9:c.1439G>T in affected families are available from the reviewed literature. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
BP2 BP2 requires observation in trans with a pathogenic variant in a healthy individual (for recessive disorders) or observation in cis with a pathogenic variant. No such observations have been reported for NM_000500.9:c.1439G>T. Details ▾Hide ▴
Evidence considered
  • No observation in trans with a pathogenic variant in a healthy individual identified.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. REVEL, BayesDel, and SpliceAI scores are unavailable for this variant due to failed genomic coordinate normalization. Without in silico predictions, BP4 cannot be assessed as met. Details ▾Hide ▴
Evidence considered
  • REVEL and BayesDel scores unavailable
  • SpliceAI data unavailable.
Still missing
  • Genomic coordinates could not be determined for in silico tool queries.
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such case has been identified in the reviewed literature for NM_000500.9:c.1439G>T. Details ▾Hide ▴
Evidence considered
  • No case with alternate molecular basis identified.

Not assessed · 2 · no assessment recorded

PS1 PS1 requires a different nucleotide change at the same codon producing the same amino acid change (p.Arg480Leu). Only c.1439G>T produces this change at codon 480; no alternative nucleotide substitution yielding p.Arg480Leu has been identified. Details ▾Hide ▴
Evidence considered
  • No alternative nucleotide change at c.1439 produces the same p.Arg480Leu substitution.
PS5 PS5 requires PM2_Supporting as a prerequisite per generic ACMG/AMP 2015 framework. PM2 is not met (variant observed in healthy population, gnomAD data unavailable), so PS5 is not applicable. Details ▾Hide ▴
Evidence considered
  • Prerequisite PM2_Supporting not met.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_000500.9:c.1439G>T is a missense change (p.Arg480Leu) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant.
Sources
pvs1_generic_framework ↗
PM3 N/ASkipped per adjudication instructions. PM3 was listed under trivially not_applicable criteria. Details ▾Hide ▴
Evidence considered
  • Skipped per adjudication instructions.
PM4 N/ASkipped per adjudication instructions. PM4 was listed under trivially not_applicable criteria. Details ▾Hide ▴
Evidence considered
  • Skipped per adjudication instructions.
PM5 N/APM5 requires a different missense change at the same amino acid residue that has been established as pathogenic. No same-residue comparator variants with established pathogenicity could be identified for position Arg480 (PM5 candidate harvesting returned no results). Details ▾Hide ▴
Evidence considered
  • No pathogenic same-residue comparators identified at Arg480.
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary known cause of disease. CYP21A2 has numerous well-characterized pathogenic missense variants that are a primary disease mechanism in congenital adrenal hyperplasia; therefore BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense variants are a well-established disease mechanism in CYP21A2.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is a single-nucleotide missense change, not an in-frame indel. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not an in-frame indel.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or the creation of a new splice site. NM_000500.9:c.1439G>T is a missense variant (p.Arg480Leu), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous/silent.

Identifiers

Gene
CYP21A2
Coding (HGVS c.)
NM_000500.9:c.1439
ClinVar
445854
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

No population statements were recorded.

Open the gnomAD-Canada detail page →

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Multiple lines of computational evidence are required for PP3. REVEL, BayesDel, and SpliceAI scores are unavailable for this variant (mutalyzer normalization did not produce the required genomic coordinates). Without in silico predictions, PP3 cannot be assessed as met. Details ▾Hide ▴
Evidence considered
  • REVEL and BayesDel scores unavailable
  • SpliceAI max delta unavailable.
Still missing
  • In silico prediction tools could not be queried
  • variant normalization to genomic coordinates was unsuccessful.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. REVEL, BayesDel, and SpliceAI scores are unavailable for this variant due to failed genomic coordinate normalization. Without in silico predictions, BP4 cannot be assessed as met. Details ▾Hide ▴
Evidence considered
  • REVEL and BayesDel scores unavailable
  • SpliceAI data unavailable.
Still missing
  • Genomic coordinates could not be determined for in silico tool queries.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or the creation of a new splice site. NM_000500.9:c.1439G>T is a missense variant (p.Arg480Leu), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous/silent.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Detection and assignment of CYP21 mutations using peptide mass signature genotyping.
    Zeng X et al. · 2004
    No paper-specific finding is recorded.
    PMID 15110320 ↗
  • Molecular model of human CYP21 based on mammalian CYP2C5: structural features correlate with clinical severity of mutations causing congenital adrenal hyperplasia.
    Robins T et al. · 2006
    No paper-specific finding is recorded.
    PMID 16788163 ↗
  • Characterization of novel missense mutations in CYP21 causing congenital adrenal hyperplasia.
    Robins T et al. · 2007
    No paper-specific finding is recorded.
    PMID 17119906 ↗
  • Linkage analysis of the C4A/C4B copy number variation and polymorphisms of the adjacent steroid 21-hydroxylase gene in a healthy population.
    Blaskó B et al. · 2009
    No paper-specific finding is recorded.
    PMID 19505723 ↗
  • A large view of CYP21 locus among Sicilians and other populations: identification of a novel CYP21A2 variant in Sicily.
    Niceta M et al. · 2011
    No paper-specific finding is recorded.
    PMID 21169732 ↗
  • Carrier testing for severe childhood recessive diseases by next-generation sequencing.
    Bell CJ et al. · 2011
    No paper-specific finding is recorded.
    PMID 21228398 ↗
  • Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene.
    Bánlaki Z et al. · 2013
    No paper-specific finding is recorded.
    PMID 23241443 ↗
  • Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia.
    Haider S et al. · 2013
    No paper-specific finding is recorded.
    PMID 23359706 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

ClinVar 3 Benign · 2 Uncertain significance · 1 Likely benign · 1 likely benign · 1 Likely Benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory) and as likely benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory). (ClinVarID = 445854)

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).