Variant classification summary

NM_000500.9: c.1493G>T

CYP21A2 · ·

GRCh37: None · GRCh38: None

Gene: CYP21A2 Transcript:

Final call

VUS

Variant details

Gene

CYP21A2

Transcript

Protein

gnomAD AF

ClinVar

None

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.(=)).

2

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

3

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

4

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.

5

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.

6

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.

7

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	The 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).	pvs1_generic_framework
PS1	N/A	PS1 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.(=)).
PS2	Not met	No de novo occurrence (with both maternity and paternity confirmed) has been reported for this variant in the literature or databases.
PS3	Not assessed	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.
PS4	Not met	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.
PS5	N/A	PS5 applies to novel missense variants at the same residue as a different pathogenic missense change. This is a 3' UTR synonymous substitution that does not alter the amino acid sequence.
PM1	Not met	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.
PM2	Not assessed	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%).
PM5	N/A	PM5 requires two different missense changes at the same amino acid residue. This variant is a synonymous 3' UTR substitution with no amino acid change (p.(=)), precluding same-residue missense comparator analysis.
PM6	Not met	No de novo observation (without confirmation of both maternity and paternity) has been reported for this variant in the literature or databases.
PP1	Not assessed	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.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a common mechanism of disease and benign missense variation is rare. This is not a missense variant; it is a synonymous substitution in the 3' UTR.
PP3	Not assessed	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.
PP4	Not assessed	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.
PP5	Not met	No reputable source (e.g., ClinGen-recognized expert panel, clinical diagnostic laboratory) has classified this variant as pathogenic. The variant has no ClinVar entry.
BA1	Not assessed	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.
BS1	Not assessed	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.
BS2	Not assessed	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.
BS3	Not assessed	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.
BS4	Not assessed	No family segregation data demonstrating lack of cosegregation with congenital adrenal hyperplasia or other CYP21A2-related phenotypes is available.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating (loss-of-function) variants cause disease. This is a synonymous 3' UTR substitution, not a missense variant.
BP2	Not assessed	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.
BP4	Not assessed	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.
BP5	Not assessed	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.
BP6	Not met	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.
BP7	N/A	BP7 is designed for coding-region synonymous (silent) variants evaluated with splicing prediction algorithms (e.g., SpliceAI) demonstrating no impact on splicing. This variant (c.*5G>T) is located in the 3' UTR, outside the coding region where canonical synonymous splicing criteria do not straightforwardly apply. No SpliceAI scores are available for this position.
BP3	N/A	Skipped per instruction — BP3 applies to in-frame indels in repetitive regions; this is a substitution variant.
PM3	N/A	Skipped per instruction — PM3 (in trans with pathogenic variant) was not assigned for assessment.
PM4	N/A	Skipped per instruction — PM4 applies to protein-length changes from indels/stop-loss; this is a substitution variant.

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