rs786204728

Variant names:

• chr6-32039807-TCGTGGAGAT-ACGAGGAGAA
• rs786204728
• NM_000500.9:c.710_719delTCGTGGAGATinsACGAGGAGAA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP2 PP5_Very_Strong

The NM_000500.9(CYP21A2):​c.710_719delTCGTGGAGATinsACGAGGAGAA​(p.IleValGluMet237AsnGluGluLys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000841747: Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID:15623806).".

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.95
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000841747: Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID: 15623806).
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.
• PP5: Variant 6-32039807-TCGTGGAGAT-ACGAGGAGAA is Pathogenic according to our data. Variant chr6-32039807-TCGTGGAGAT-ACGAGGAGAA is described in ClinVar as Pathogenic. ClinVar VariationId is 189145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.710_719delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet237AsnGluGluLys	missense	N/A	NP_000491.4
	CYP21A2	NM_001128590.4		c.620_629delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet207AsnGluGluLys	missense	N/A	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.305_314delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet102AsnGluGluLys	missense	N/A	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.710_719delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet237AsnGluGluLys	missense	N/A	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.710_719delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet237AsnGluGluLys	missense	N/A	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.710_719delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet237AsnGluGluLys	missense	N/A	ENSP00000630656.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

Splicing

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

Other links and lift over

dbSNP: rs786204728; hg19: chr6-32007584;