CYP21A2 c.1493G>TUncertain significance

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Variant interpretation report

CYP21A2 c.1493G>T

NM_000500.9: c.1493G>T View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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: 0

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: none; combination = no applied criteria, which maps to VUS.

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

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

No listed criterion applied gnomAD-Canada ↗

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

No screenshot for this evidence

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

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 ↗

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: 0 met · 6 not met · 13 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000500.9:c.1493G>T is a synonymous substitution in the 3' untranslated region of CYP21A2 (c.*5G>T), with no predicted amino acid change (p.(=)).

CYP21A2 encodes 21-hydroxylase; loss-of-function variants cause autosomal recessive congenital adrenal hyperplasia (21-hydroxylase deficiency).

This variant is absent from ClinVar; no clinical classification has been asserted by any submitter or expert panel.

Population frequency data is unavailable for this 3' UTR position: gnomAD v2.1 and v4.1 returned no data, and gnomAD-Canada shows zero coverage, precluding PM2/BA1/BS1 assessment.

No functional studies, case-control data, de novo reports, segregation analyses, or in silico predictions specific to this 3' UTR variant have been identified in the literature or public databases.

PVS1 is not applicable as this is not a null variant (nonsense, frameshift, or canonical splice site change). PS1, PS5, PM5, PP2, BP1, and BP7 are not applicable as this variant is not a missense or coding-synonymous change.

The variant cannot be classified at this time due to insufficient evidence across all applicable ACMG/AMP criteria. It remains a variant of uncertain significance (VUS) by default under generic ACMG/AMP 2015 rules, given the absence of both pathogenic and benign evidence.

Not met · 6 · evaluated, threshold not reached

PS2 No de novo occurrence (with both maternity and paternity confirmed) has been reported for this variant in the literature or databases. Details ▾Hide ▴

Still missing

No de novo data available in public databases or literature

PS4 No case-control studies or statistically significant enrichment of this variant in affected individuals compared to population controls has been demonstrated. No patient observations have been reported in ClinVar or the literature. Details ▾Hide ▴

Still missing

No case-control or enrichment data available

PM1 This variant is located at c.*5 in the 3' UTR, not within a known functional domain, critical residue, or established mutational hotspot in the CYP21A2 gene. No hotspot data identifies this position as significant. Details ▾Hide ▴

Evidence considered

Variant is in the 3' UTR
no hotspot or domain evidence at this position

PM6 No de novo observation (without confirmation of both maternity and paternity) has been reported for this variant in the literature or databases. Details ▾Hide ▴

Still missing

No de novo data available

PP5 No reputable source (e.g., ClinGen-recognized expert panel, clinical diagnostic laboratory) has classified this variant as pathogenic. The variant has no ClinVar entry. Details ▾Hide ▴

Evidence considered

No ClinVar entry
no expert panel classification

BP6 No reputable source (e.g., ClinGen-recognized expert panel, clinical diagnostic laboratory) has classified this variant as benign without accessible evidence. The variant has no ClinVar entry. Details ▾Hide ▴

Evidence considered

No ClinVar entry
no expert panel benign classification

Not assessed · 13 · no assessment recorded

PS3 No functional studies evaluating the impact of this 3' UTR variant on mRNA stability, miRNA binding, splicing, or protein expression have been identified in the literature or in curated functional databases. Details ▾Hide ▴

Still missing

No in vitro or in vivo functional data available
3' UTR-specific assays (e.g.
luciferase reporter
RNA stability) would be required

PM2 Population frequency data is unavailable for this 3' UTR position. gnomAD v2.1 and v4.1 returned no data (null allele counts and frequencies). gnomAD-Canada reports zero coverage (AC=0, AN=0), which indicates the position was not successfully genotyped rather than true absence from the population. The variant cannot be evaluated against the PM2 threshold (<0.1%). Details ▾Hide ▴

Evidence considered

gnomAD v2.1 and v4.1: no data
gnomAD-Canada: zero coverage (ac=0
an=0)

Still missing

Population frequency data for this 3' UTR position is unavailable in standard databases

PP1 No family cosegregation data is available for this variant. Segregation analysis in families with congenital adrenal hyperplasia or other CYP21A2-related phenotypes has not been reported. Details ▾Hide ▴

Still missing

No family segregation studies available

PP3 Standard in silico prediction tools (REVEL, BayesDel, SpliceAI, HCI prior) do not apply to this 3' UTR variant and returned no scores. Tools specific to 3' UTR regulatory element prediction (e.g., miRNA binding site analysis, RNA secondary structure prediction) were not evaluated in this assessment. Details ▾Hide ▴

Evidence considered

REVEL: not available
BayesDel: not available
SpliceAI: no scores
HCI prior: not available

Still missing

No in silico prediction data for 3' UTR regulatory elements
dedicated tools (RegRNA
TargetScan
RNAfold) could be pursued

PP4 No patient phenotype or family history data specific to this variant has been reported in the literature or clinical databases. CYP21A2 is associated with congenital adrenal hyperplasia (21-hydroxylase deficiency), but no affected individuals carrying this variant have been described. Details ▾Hide ▴

Still missing

No patient phenotype data available for carriers of this variant

BA1 No population allele frequency data is available to evaluate whether this variant exceeds the BA1 threshold (>1% per generic ACMG cutoff). gnomAD v2.1 and v4.1 returned no data for this position, and gnomAD-Canada shows zero coverage. Details ▾Hide ▴

Evidence considered

No usable population frequency data

Still missing

Population frequency data not available for this 3' UTR position

BS1 No population allele frequency data is available to evaluate whether this variant exceeds the BS1 threshold (>0.3% per generic ACMG cutoff). The expected prevalence of congenital adrenal hyperplasia due to CYP21A2 variants is low, but absence of frequency data precludes assessment. Details ▾Hide ▴

Evidence considered

No usable population frequency data

Still missing

Population frequency data not available for this 3' UTR position

BS2 No data regarding observation of this variant in healthy adult individuals is available. For a recessive disorder like congenital adrenal hyperplasia, observation in trans with a pathogenic variant in a healthy individual would be informative, but no such data exists. Details ▾Hide ▴

Still missing

No healthy control observation data available

BS3 No functional studies demonstrating a neutral (non-damaging) effect of this 3' UTR variant on gene expression, mRNA stability, or protein function have been identified. Details ▾Hide ▴

Still missing

No functional data demonstrating neutral effect

BS4 No family segregation data demonstrating lack of cosegregation with congenital adrenal hyperplasia or other CYP21A2-related phenotypes is available. Details ▾Hide ▴

Still missing

No segregation data for non-cosegregation assessment

BP2 No data on observation of this variant in trans with a known pathogenic CYP21A2 variant in an unaffected individual is available. Such an observation would support a benign interpretation in this autosomal recessive disorder. Details ▾Hide ▴

Still missing

No data on trans observation in unaffected individuals

BP4 Standard computational prediction tools (REVEL, BayesDel, SpliceAI) do not apply to this 3' UTR variant and returned no scores. No multiple lines of computational evidence are available to suggest a neutral effect on gene product. Details ▾Hide ▴

Evidence considered

No in silico scores available

Still missing

No computational evidence to assess neutral effect

BP5 No observation of this variant in a case with an alternative molecular cause for the phenotype (e.g., a different confirmed pathogenic variant in CYP21A2 or another gene) has been reported. Details ▾Hide ▴

Still missing

No data on co-occurrence with alternative molecular diagnoses

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThe variant is NM_000500.9:c.*5G>T, a synonymous substitution located in the 3' untranslated region (5 nucleotides downstream of the stop codon). It does not fall into the PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 framework (PMC6185798). The generic PVS1 framework confirms non-applicability (variant_bucket: 'other', apply_generic_pvs1_framework: false). Details ▾Hide ▴

Evidence considered

Variant is in 3' UTR
not a null variant
protein consequence is p.(=)

Sources

pvs1_generic_framework ↗

PS1 N/APS1 applies to missense variants where the same amino acid change as a previously established pathogenic variant has occurred via a different nucleotide change. This is a 3' UTR variant that does not alter the amino acid sequence (p.(=)). Details ▾Hide ▴