rs387906510

Variant names:

• chr6-32039132-GGAGACTAC-G
• rs387906510
• NM_000500.9:c.332_339delGAGACTAC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000500.9(CYP21A2):​c.332_339delGAGACTAC​(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:13
• Conservation: PhyloP100: 3.83
• Publications: 26 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), 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 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 VariationId is 12164.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.332_339delGAGACTAC	p.Gly111ValfsTer21	frameshift_variant	Exon 3 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.242_249delGAGACTAC	p.Gly81ValfsTer21	frameshift_variant	Exon 2 of 9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-74_-67delGAGACTAC		5_prime_UTR_variant	Exon 3 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-74_-67delGAGACTAC		5_prime_UTR_variant	Exon 2 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.332_339delGAGACTAC	p.Gly111ValfsTer21	frameshift_variant	Exon 3 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151892 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 246380 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.0000225 AC: 1 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26050

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110916

Other (OTH) AF: 0.00 AC: 0 AN: 60302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41338

American (AMR) AF: 0.000525 AC: 8 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000612 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:9

Aug 29, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

May 19, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3 -

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 17, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 01, 2022

Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM#201910) and hyperandrogenism nonclassic type due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 16 heterozygotes, 0 homozygotes). However, please note this variant has failed a filter used for quality control in gnomAD v3. (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple compound heterozygous patients (ClinVar, PMIDs: 35079965, 26804566). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 10, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP5 -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2+PM3_VeryStrong+PVS1 -

not provided Pathogenic:4

Sep 13, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs387906510; hg19: chr6-32006909;