Genetic Variant CYP21A2:p.Val282Leu (chr6-32040110-GTG-CTT) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is The variant received 12 classification points (ACMG Germline Pathogenicity v2019): 12P and 0B. PS1_Very_StrongPM1PM2

The NM_000500.9(CYP21A2):c.844_846delGTGinsCTT (p.Val282Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V282L: not_provided (ClinVar VariationId 65610) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Adrenal hyperplasia 3 (AH3).

Frequency

Genomes: not found (cov: 32)

Consequence

CYP21A2
NM_000500.9 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.53

Publications

0 publications found

Variant links:

Genes affected

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A member 2) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYP21A2 Gene-Disease associations (from GenCC):

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Myriad Women's Health, Labcorp Genetics (formerly Invitae)
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP21A2 links:

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new If you want to explore the variant's impact on the transcript NM_000500.9, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 points.

PS1

Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).

PM1

Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 0 benign (OR vs. background: 25.0).

PM2

Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (base 0.001, raised to 0.005 by highest known P/LP ClinVar AF 0.00716) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000500.9. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP21A2	NM_000500.9	MANE Select	c.844_846delGTGinsCTT	p.Val282Leu	missense	N/A	NP_000491.4
CYP21A2	NM_001128590.4		c.754_756delGTGinsCTT	p.Val252Leu	missense	N/A	NP_001122062.3	P08686-2
CYP21A2	NM_001368143.2		c.439_441delGTGinsCTT	p.Val147Leu	missense	N/A	NP_001355072.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP21A2	ENST00000644719.2	MANE Select	c.844_846delGTGinsCTT	p.Val282Leu	missense	N/A	ENSP00000496625.1	P08686-1
CYP21A2	ENST00000960600.1		c.880_882delGTGinsCTT	p.Val294Leu	missense	N/A	ENSP00000630659.1
CYP21A2	ENST00000960597.1		c.853_855delGTGinsCTT	p.Val285Leu	missense	N/A	ENSP00000630656.1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over