rs397509367

Variant names:

• chr6-32041097-GG-C
• rs397509367
• NM_000500.9:c.1451_1452delGGinsC

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PVS1_Strong PM2 PP2 PP5_Very_Strong

The NM_000500.9(CYP21A2):​c.1451_1452delGGinsC​(p.Arg484ProfsTer58) variant causes a frameshift, 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R484W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP21A2 NM_000500.9 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.19
• Publications: 6 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]

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNXB Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, PanelApp Australia
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• 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 6-32041097-GG-C is Pathogenic according to our data. Variant chr6-32041097-GG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12157.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.1451_1452delGGinsC	p.Arg484ProfsTer58	frameshift missense	Exon 10 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.1361_1362delGGinsC	p.Arg454ProfsTer58	frameshift missense	Exon 9 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.1046_1047delGGinsC	p.Arg349ProfsTer58	frameshift missense	Exon 10 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.1451_1452delGGinsC	p.Arg484ProfsTer58	frameshift missense	Exon 10 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.1487_1488delGGinsC	p.Arg496ProfsTer58	frameshift missense	Exon 10 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.1460_1461delGGinsC	p.Arg487ProfsTer58	frameshift missense	Exon 10 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (3)
2	-	-	not provided (2)
1	-	-	CYP21A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=1/199	disease causing

Splicing

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

Other links and lift over

dbSNP: rs397509367; hg19: chr6-32008874;