NM_000500.9:c.710_719delTCGTGGAGATinsACGAGGAGAA

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 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. Variant has been reported in ClinVar as Pathogenic (★★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 22) in uniprot entity CP21A_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000500.9
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-32039807-TCGTGGAGAT-ACGAGGAGAA is Pathogenic according to our data. Variant chr6-32039807-TCGTGGAGAT-ACGAGGAGAA is described in ClinVar as [Pathogenic]. Clinvar id is 189145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.710_719delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet237AsnGluGluLys	missense_variant		ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.620_629delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet207AsnGluGluLys	missense_variant			NP_001122062.3
CYP21A2	NM_001368143.2	c.305_314delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet102AsnGluGluLys	missense_variant			NP_001355072.1
CYP21A2	NM_001368144.2	c.305_314delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet102AsnGluGluLys	missense_variant			NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.710_719delTCGTGGAGATinsACGAGGAGAA	p.IleValGluMet237AsnGluGluLys	missense_variant			NM_000500.9	ENSP00000496625.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:1

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000500.7(CYP21A2):c.(710T>A;713T>A;719T>A)(I237N;V238E;M240K) is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 2845408, 23359698 and 2249999. Classification of NM_000500.7(CYP21A2):c.(710T>A;713T>A;719T>A)(I237N;V238E;M240K) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:1

Oct 17, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in a genomic region of low or unreliable sequencing quality, and therefore estimations of its population frequency are uninformative in assessment of variant pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant consists of three missense changes: p.Ile237Asn, p.Val238Glu, and p.Met240Lys, and has been referred to as the "exon 6 cluster" or the "E6 cluster" in published literature. In multiple individuals with congenital adrenal hyperplasia, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID: 15623806). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204728; hg19: chr6-32007584;