rs387906510

chr6-32039132-GGAGACTAC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000500.9(CYP21A2):c.332_339del(p.Gly111ValfsTer21) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.83

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-32039132-GGAGACTAC-G is Pathogenic according to our data. Variant chr6-32039132-GGAGACTAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 12164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039132-GGAGACTAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.332_339del	p.Gly111ValfsTer21	frameshift_variant	3/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.242_249del	p.Gly81ValfsTer21	frameshift_variant	2/9
CYP21A2	NM_001368143.2	c.-74_-67del		5_prime_UTR_variant	3/10
CYP21A2	NM_001368144.2	c.-74_-67del		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.332_339del	p.Gly111ValfsTer21	frameshift_variant	3/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 16 AN: 151892 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000164 AC: 24 AN: 1459358 Hom.: 0 AF XY: 0.0000138 AC XY: 10 AN XY: 725596

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000105 AC: 16 AN: 151892 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74194

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000525

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000612 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: CYP21A2 c.332_339delGAGACTAC (p.Gly111ValfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 246380 control chromosomes (gnomAD). c.332_339delGAGACTAC has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Congenital Adrenal Hyperplasia (Wilson_2007, Milacic_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and results in null activity based on in vitro studies. Five ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 29, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 19, 2023	PVS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_000500.7(CYP21A2):c.332_339del8(G111Vfs*21) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with classic disease. Sources cited for classification include the following: PMID 25227725, 8081391, 23359698, 25121463 and 12788880 . Classification of NM_000500.7(CYP21A2):c.332_339del8(G111Vfs*21) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 07, 2023	The c.332_339del (p.Gly111Valfs*21) (also known as c.332_339del8 (G110del8nt)) variant alters the translational reading frame of the CYP21A2 mRNA and causes the premature termination of CYP21A2 protein synthesis. This pathogenic variant is associated with salt wasting CAH (PMIDs: 2827462 (1988), 23359698 (2013), and 25227725 (2014)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 07, 2023	This variant is expected to result in the loss of a functional protein. 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. In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. In some published literature, this variant is referred to as c.329_336del, g.707_714del, p.Gly110fs, or as the 8 bp deletion in exon 3. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change creates a premature translational stop signal (p.Gly111Valfs*21) in the CYP21A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP21A2 are known to be pathogenic (PMID: 10857554). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 7749410, 8081391, 23359698, 25227725, 26804566). This variant is also known as 706del8, 707_714del8, E3del8bp, c.711_718delGAGACTAC. ClinVar contains an entry for this variant (Variation ID: 12164). For these reasons, this variant has been classified 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: rs387906510; hg19: chr6-32006909;