About CYP21A2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CYP21A2 c.1A>G, p.(Met1?)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
c.1A>G (p.Met1Val) is a start-loss variant abolishing the translation initiation codon of CYP21A2, a gene in which loss of function is a well-established mechanism for autosomal recessive congenital adrenal hyperplasia due to 21-hydroxylase deficiency. No alternative in-frame translation initiation codon has been identified in CYP21A2. Published evidence confirms that start codon mutations in CYP21A2 (including c.1A>G, M1I, and c.2T>C) result in complete loss of 21-hydroxylase enzymatic activity, consistent with PVS1_VeryStrong per ClinGen SVI framework (PMC6185798).
PM2Supporting
PM2 · supporting
c.1A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 threshold (<0.1% allele frequency). Although the ClinVar submitter noted that gnomAD frequency data may be unreliable in this region due to pseudogene (CYP21A1P) homology, the variant is consistently absent across all population databases.
PP5Supporting
PP5 · supporting
c.1A>G is classified as Pathogenic in ClinVar (Variation ID 1451630, submitted by Labcorp Genetics/Invitae) and independently classified as Pathogenic in a published study (PMID:31006099, Dundar et al. 2019). Although the ClinVar review status is criteria provided, single submitter, the independent corroboration from a peer-reviewed publication supports PP5 at the supporting level.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; combination = 1 very strong + 2 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 3 met · 19 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
c.1A>G (p.Met1Val) is a start-loss variant that abolishes the translation initiation codon of CYP21A2, a gene in which loss of function is a well-established mechanism for autosomal recessive congenital adrenal hyperplasia (21-hydroxylase deficiency).
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.
c.1A>G is classified as Pathogenic in ClinVar (Variation ID 1451630, submitted by Labcorp Genetics/Invitae) and independently reported as Pathogenic in a peer-reviewed study of CAH patients in the Anatolian population.
Published evidence confirms that start codon mutations in CYP21A2 (including c.1A>G, M1I, and c.2T>C) result in complete loss of 21-hydroxylase enzymatic activity, with c.1A>G specifically associated with salt-wasting CAH.
Applying generic ACMG/AMP 2015 combination rules: PVS1_VeryStrong (1) + PM2_Supporting (1) + PP5_Supporting (1) meets the threshold for Pathogenic classification (1 Very Strong + ≥2 Supporting).
No criteria match.
Met · 3
PVS1 Very strongc.1A>G (p.Met1Val) is a start-loss variant abolishing the translation initiation codon of CYP21A2, a gene in which loss of function is a well-established mechanism for autosomal recessive congenital adrenal hyperplasia due to 21-hydroxylase deficiency. No alternative in-frame translation initiation codon has been identified in CYP21A2. Published evidence confirms that start codon mutations in CYP21A2 (including c.1A>G, M1I, and c.2T>C) result in complete loss of 21-hydroxylase enzymatic activity, consistent with PVS1_VeryStrong per ClinGen SVI framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- c.1A>G abolishes the ATG initiation codon (p.Met1Val / p.M1?)
- CYP21A2 loss of function is a well-established disease mechanism for autosomal recessive CAH
- PMID:31006099 reports c.1A>G (p.M1V) as pathogenic in a CAH patient
- PMID:23142378 cites c.1A>G as associated with salt-wasting CAH (Rabbani et al. 2012)
- Analogous start codon mutations M1I and c.2T>C are confirmed to abolish protein translation and enzymatic activity
- No evidence of an alternative in-frame translation initiation codon in CYP21A2
Sources
PM2 Supportingc.1A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 threshold (<0.1% allele frequency). Although the ClinVar submitter noted that gnomAD frequency data may be unreliable in this region due to pseudogene (CYP21A1P) homology, the variant is consistently absent across all population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (genomes)
Still missing
- Pseudogene homology in CYP21A2 region may affect gnomAD variant calling sensitivity
Sources
PP5 Supportingc.1A>G is classified as Pathogenic in ClinVar (Variation ID 1451630, submitted by Labcorp Genetics/Invitae) and independently classified as Pathogenic in a published study (PMID:31006099, Dundar et al. 2019). Although the ClinVar review status is criteria provided, single submitter, the independent corroboration from a peer-reviewed publication supports PP5 at the supporting level. Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic
- Variation ID 1451630 (Labcorp/Invitae)
- PMID:31006099: classified as Pathogenic per ACMG guidelines
Sources
Not met · 19 · evaluated, threshold not reached
PS1 PS1 requires a same-amino-acid change as a previously established pathogenic variant. c.1A>G results in p.Met1Val (start-loss), while other known pathogenic start codon variants in CYP21A2 are p.Met1Ile (M1I, c.3G>A) and p.Met1Thr (M1T, c.2T>C). These are different amino acid changes, so PS1 does not apply. Details ▾Hide ▴
No further detail was recorded.
PS2 No de novo occurrence data are available for c.1A>G. Parental testing was not reported in any of the reviewed publications for this specific variant. Details ▾Hide ▴
Still missing
- No de novo data available for this variant
PS3 No direct functional studies of c.1A>G were identified. PMID:14676460 provides indirect functional evidence that start codon mutations in CYP21A2 abolish translation (M1I studied, not c.1A>G), but this does not meet the threshold for variant-specific PS3 functional evidence. Details ▾Hide ▴
Evidence considered
- PMID:14676460 demonstrated that an M1I start codon mutation abolishes CYP21A2 translation — analogous but not variant-specific
Still missing
- No variant-specific functional assay (enzymatic activity
- protein expression) for c.1A>G
Sources
PS4 c.1A>G has been observed in at least one CAH patient (PMID:31006099, heterozygous), and is absent from gnomAD. However, a single observation does not provide statistically significant case-control evidence required for PS4. Details ▾Hide ▴
Evidence considered
- Observed in 1 CAH patient (heterozygous) in PMID:31006099
- Absent from gnomAD v2.1 and v4.1
Still missing
- Insufficient case count for statistical enrichment analysis
- No control cohort comparison data
Sources
PM1 This variant does not lie in a mutational hotspot. Cancer Hotspots analysis did not identify the residue as statistically significant, and no CYP21A2-specific functional domain hotspots have been defined for this gene. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- exact variant not listed
PM6 No de novo occurrence data are available for c.1A>G. Parental testing was not reported for this variant in any reviewed publication. Details ▾Hide ▴
Still missing
- No de novo confirmation for this variant
PP1 No segregation data are available for c.1A>G. Although the ClinVar submission (SCV002230679) mentions segregation with disease in related individuals, no specific segregation data were identified in the reviewed literature for this exact variant. The c.2T>C variant (PMID:23142378) showed segregation in 6 families, but this is a different nucleotide change. Details ▾Hide ▴
Evidence considered
- ClinVar submission mentions segregation but provides no specific data for c.1A>G
Still missing
- No published segregation data for c.1A>G
Sources
PP2 PP2 is designed for missense variants in genes with a low rate of benign missense variation. This is a start-loss variant, not a missense substitution, and PP2 is not appropriately applied to loss-of-initiation-codon events. Details ▾Hide ▴
No further detail was recorded.
PP3 In silico predictors do not support a deleterious effect for this start-loss variant in a way that PP3 was designed to assess. REVEL score is 0.414 (below the 0.5 pathogenic threshold), BayesDel score is 0.25807 (low), and SpliceAI delta score is 0.00. PP3 is intended for missense variants with multiple lines of computational evidence supporting pathogenicity, and these tools are not optimized for start-loss variants. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.414
- BayesDel score: 0.25807
- SpliceAI max delta: 0.00
Sources
PP4 The variant was identified in a CAH patient cohort (PMID:31006099), but specific phenotypic details for the c.1A>G carrier are not reported in sufficient detail to meet PP4. The patient was part of a CAH study, but individualized clinical features (age, sex, CAH subtype, 17-OHP levels) are not provided for this specific variant carrier. Details ▾Hide ▴
Evidence considered
- c.1A>G detected in 1 individual within a CAH patient cohort
Still missing
- No patient-specific phenotype details available for the c.1A>G carrier
Sources
BA1 c.1A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The BA1 threshold of >1% allele frequency is not met. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0% across all population databases
Sources
BS1 c.1A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The BS1 threshold of >0.3% allele frequency is not met. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0% across all population databases
Sources
BS2 No evidence of observation in healthy homozygous adults. The variant is absent from gnomAD and has been observed only in heterozygous state in affected CAH patients. Details ▾Hide ▴
Still missing
- No healthy homozygous observations reported
BS3 No functional studies demonstrating a benign or neutral effect of c.1A>G exist. Published evidence on analogous start codon mutations in CYP21A2 indicates complete loss of function, which is inconsistent with a benign functional effect. Details ▾Hide ▴
Evidence considered
- Analogous start codon mutations (M1I
- c.2T>C) result in loss of protein function
- not normal activity
Sources
BS4 No evidence of non-segregation with disease. All available evidence supports association of start codon mutations in CYP21A2 with CAH. Details ▾Hide ▴
No further detail was recorded.
BP2 No evidence of c.1A>G observed in trans with a known pathogenic CYP21A2 variant in a healthy individual. Such an observation would be inconsistent with the autosomal recessive disease mechanism. Details ▾Hide ▴
Still missing
- No co-occurrence data in healthy individuals
BP4 Multiple lines of computational evidence do not support a benign interpretation. REVEL (0.414) and BayesDel (0.25807) scores are not strongly predictive in either direction. SpliceAI (max delta 0.00) predicts no splicing impact, which is expected for a start codon variant. These in silico tools are not optimized for start-loss variants, and their intermediate scores do not constitute evidence for benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.414 (below pathogenic threshold of 0.5)
- BayesDel: 0.25807 (low)
- SpliceAI max delta: 0.00
Sources
BP5 No alternative molecular basis for disease has been identified that would argue against the pathogenicity of c.1A>G. The variant is consistently classified as pathogenic in ClinVar and published literature. Details ▾Hide ▴
No further detail was recorded.
BP6 No reputable source reports c.1A>G as benign or likely benign. ClinVar classifies it as Pathogenic, and PMID:31006099 classifies it as Pathogenic. Details ▾Hide ▴
Evidence considered
- All available classifications are pathogenic
- not benign
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/APM5 is not applicable to start-loss variants. The variant is at the initiator methionine codon, and no same-residue missense comparator exists at the start codon position. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where a truncating mechanism is known to cause disease. c.1A>G is itself a start-loss (truncating equivalent) variant, not a missense variant, so BP1 does not apply. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped — not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. c.1A>G is a start-loss missense variant, not a synonymous change, and BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not applicable to start-loss variants; it applies only to missense variants where a different pathogenic amino acid change exists at the same residue. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CYP21A2
- Transcript
- NM_000500.9
- Coding (HGVS c.)
- NM_000500.9:c.1A>G
- Protein (HGVS p.)
- NP_000491.4:p.(Met1?)
- GRCh38
- chr6:32038423 A>G
- GRCh37
- chr6:32006200 A>G
- ClinVar
- 1451630
Gene diagram
Every interpreted variant in CYP21A2, mapped onto the exon structure of NM_000500.9. Select a row to find it on the plot.
CYP21A2NM_000500.9
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CYP21A2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.414
- BayesDel
- 0.258
How the predictions were used
PP3 In silico predictors do not support a deleterious effect for this start-loss variant in a way that PP3 was designed to assess. REVEL score is 0.414 (below the 0.5 pathogenic threshold), BayesDel score is 0.25807 (low), and SpliceAI delta score is 0.00. PP3 is intended for missense variants with multiple lines of computational evidence supporting pathogenicity, and these tools are not optimized for start-loss variants. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.414
- BayesDel score: 0.25807
- SpliceAI max delta: 0.00
Sources
BP4 Multiple lines of computational evidence do not support a benign interpretation. REVEL (0.414) and BayesDel (0.25807) scores are not strongly predictive in either direction. SpliceAI (max delta 0.00) predicts no splicing impact, which is expected for a start codon variant. These in silico tools are not optimized for start-loss variants, and their intermediate scores do not constitute evidence for benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.414 (below pathogenic threshold of 0.5)
- BayesDel: 0.25807 (low)
- SpliceAI max delta: 0.00
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. c.1A>G is a start-loss missense variant, not a synonymous change, and BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.414. BayesDel score = 0.25807.
5 paper records listed. 2 cited in the classification.
Cited in the classification
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PMID 23142378 ↗Investigation of CYP21A2 mutations in Turkish patients with 21-hydroxylase deficiency and a novel founder mutation.Toraman B et al. · 2013 Jan 15Investigated CYP21A2 mutations in 48 Turkish CAH patients. Identified c.2T>C (p.M1?) as a novel founder mutation in 6 families (13.3% of mutant alleles), associated with classical CAH (salt-wasting in 5, simple virilizing in 1). In the discussion, c.1A>G is cited as being associated with salt-wasting CAH in an Iranian patient (Rabbani et al. 2012), supporting that disruption of the translation initiation codon causes severe disease.→ PVS1 Names this variant
Source detail
disruption of the first position of translation initiation codon, c.1A>G was shown to be associated with salt wasting form of 21OHD CAH in a patient from Iranian population as well (Rabbani et al., 2012)
Location Abstract; Results para 5-6; Table 1; Discussion para 3 (lines 623-625)
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PMID 31006099 ↗The molecular basis and genotype-phenotype correlations of congenital adrenal hyperplasia (CAH) in Anatolian population.Dundar A et al. · 2019 AugComprehensive molecular analysis of CAH-associated genes (CYP21A2, CYP11B1, HSD3B2) in 365 Anatolian individuals. c.1A>G (p.M1V) was detected in heterozygous state in one CAH patient and classified as Pathogenic per ACMG guidelines. The variant was absent from population databases (ExAC, 1000 Genomes). The variant is identified as causing start loss and was among 9 CYP21A2 variants classified as Pathogenic in this study.→ PVS1 → PM2 → PP5 Names this variant
Source detail
p.M1 V [34, 35] / c.1A>G / Exon 1 / Missense, start loss ... Pathogenic / Pathogenic
Location Table 2, variant #16 (lines 501-510); Results section (lines 688-694)
Other recorded publications
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PMID 14676460 ↗Three novel mutations in Japanese patients with 21-hydroxylase deficiency.Usui T et al. · 2004Analyzed CYP21A2 mutations in 36 Japanese CAH patients and identified three novel mutations, including M1I (c.3G>A, ATG→ATA) at the initiation codon in exon 1. The M1I patient was a compound heterozygote with IVS2-13A/C>G and presented with salt-wasting CAH. The authors concluded the M1I start codon mutation abolishes translation and results in zero predicted enzymatic activity.Does not name this variant
Quoted passage
The first novel mutation was at codon 1 (ATG-ATA) in exon 1, which caused an amino acid substitution from methionine to isoleucine
Abstract; Results para 1-2; Table 1; Discussion para 3-4; Figure 2
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PMID 25227725 ↗The frequency and the effects of 21-hydroxylase gene defects in congenital adrenal hyperplasia patients.Kirac D et al. · 2014Characterized CYP21A2 mutations in 124 Turkish CAH patients by direct sequencing and MLPA. Identified c.2T>C (start codon change) as a novel variant. NM_000500.9:c.1A>G was not identified or discussed in this study.Does not name this variant
Quoted passage
120 T>C (c.2T>C) ... Start codon location changes
Table 1 (nucleotide position 120 T>C corresponds to c.2T>C, not c.1A>G)
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Presents the Sherloc framework for refining ACMG-AMP variant classification criteria. This is a methodological paper that does not discuss any specific CYP21A2 variants, including c.1A>G.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1451630/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-32006200-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-32038423-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-32038423-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000500.9%3Ac.1A%3…
- OncoKB ↗www.oncokb.org/gene/CYP21A2/M1?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CYP21A2+c.1A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 1451630)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.414. BayesDel score = 0.25807.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.