rs397509367

chr6-32041096-CGG-CC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000500.9(CYP21A2):c.1451_1452delinsC(p.Arg484ProfsTer58) variant causes a frameshift 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP21A2 NM_000500.9 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.19

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 14 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-32041097-GG-C is Pathogenic according to our data. Variant chr6-32041097-GG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.1451_1452delinsC	p.Arg484ProfsTer58	frameshift_variant	10/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.1361_1362delinsC	p.Arg454ProfsTer58	frameshift_variant	9/9
CYP21A2	NM_001368143.2	c.1046_1047delinsC	p.Arg349ProfsTer58	frameshift_variant	10/10
CYP21A2	NM_001368144.2	c.1046_1047delinsC	p.Arg349ProfsTer58	frameshift_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.1451_1452delinsC	p.Arg484ProfsTer58	frameshift_variant	10/10		NM_000500.9	P1

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Mar 10, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 09, 2023	The CYP21A2 c.1451_1452delinsC (p.Arg484Profs*58) variant alters the translational reading frame of the CYP21A2 mRNA and causes the premature termination of CYP21A2 protein synthesis. This variant has been reported in the published literature in individuals affected with CAH and is usually associated with a salt-wasting phenotype, although the nonclassic CAH phenotype has also been reported (PMIDs: 30995443 (2019), 26206692 (2015), 24904866 (2013), 22020670 (2012), 1496017 (1992)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 09, 2023	Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity. This variant is expected to disrupt protein function. In multiple individuals with congenital adrenal hyperplasia, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2. In some published literature, this variant is referred to as a frameshift at codon 483. -

CYP21A2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The CYP21A2 c.1451_1452delinsC variant is predicted to result in a frameshift and premature protein termination (p.Arg484Profs*58). This patient is heterozygous in the CYP21A2 gene for a rarer pathogenic variant defined as c.1451_1452delinsC, which is predicted to results in a frameshift and an extended protein beyond the normal stop codon (p.Arg484Profs*58). This variant has been documented to be associated with salt-wasting (SW) congenital adrenal hyperplasia (CAH) (Hong et al. 2015. PubMed ID: 26206692; Xu et al. 2019. PubMed ID: 30995443; Hou et al. 2019. PubMed ID: 31446012). This variant is interpreted as pathogenic. -

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: rs397509367; hg19: chr6-32008874;