chr6-32038514-C-T

Position:

• chr6-32038514-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5 PP5_Very_Strong

The NM_000500.9(CYP21A2):​c.92C>T​(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,607,244 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 2.34

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 10 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-32038514-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 988330.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 6-32038514-C-T is Pathogenic according to our data. Variant chr6-32038514-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32038514-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.92C>T	p.Pro31Leu	missense_variant	1/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.92C>T	p.Pro31Leu	missense_variant	1/9
CYP21A2	NM_001368143.2	c.-333C>T		5_prime_UTR_variant	1/10
CYP21A2	NM_001368144.2	c.-243C>T		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.92C>T	p.Pro31Leu	missense_variant	1/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 152008 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.0000916 AC: 22 AN: 240194 Hom.: 0 AF XY: 0.0000690 AC XY: 9 AN XY: 130478

Gnomad AFR exome AF: 0.000334

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000934

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1455118 Hom.: 1 Cov.: 107 AF XY: 0.0000899 AC XY: 65 AN XY: 723376

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.0000956

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152126 Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74378

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000530

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000528 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:5 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 28, 2017	This variant has been reported in 1000 genomes database, dbSNP(rs9378251) and HGMD. The in silico prediction of this variant is disease-causing by MutationTaster. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	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) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 77 heterozygotes, 1 homozygote). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple patients (ClinVar, PMIDs: 35079965, 26804566). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. It has been shown to cause 30-60% loss of 21-hydroxylase enzymatic activity (PMID: 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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_000500.7(CYP21A2):c.92C>T(P31L) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 23142378, 16427797, 23359698, 1644925, 2072928 and 9215318. Classification of NM_000500.7(CYP21A2):c.92C>T(P31L) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 28, 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 (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. This variant has been reported to associate with non-classic congenital adrenal hyperplasia (CAH). In some published literature, this variant is referred to as Pro30Leu or *8. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies have shown this variant significantly reduces enzymatic activity (PMID: 20080860, 23927611, 24953648, 28539365). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 28, 2023	In the published literature, this variant has been reported in a non-classic phenotype of congenital adrenal hyperplasia (CAH) (PMID: 2072928 (1991)). It has also been seen in many affected individuals with either a salt-wasting or simple virilizing phenotype as a result of being carried in combination with different pathogenic variants (PMIDs: 22629504 (2012), 26425475 (2015), and 27041116 (2016)). Functional studies have shown this variant significantly reduces enzymatic activity (PMIDs: 20080860 (2010), 23927611 (2014), 24953648 (2015), and 28539365 (2017)). The variant under the control of the CYP21A2 gene promoter has been reported to cause a less severe phenotype than under the control of the CYP21A pseudogene promoter (PMID: 15670187 (2005)). The frequency of this variant in the general population, 0.00059 (14/23690 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the CYP21A2 protein (p.Pro31Leu). 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 missense change has been observed in individual(s) with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 2072928, 23142378, 23359698, 26804566, 31446012). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as P30L. ClinVar contains an entry for this variant (Variation ID: 12153). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2072928, 28539365). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Benign	0.085	.;.;.;T;.;.
Eigen	Benign	0.020
Eigen_PC	Benign	-0.0015
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.78	.;.;T;T;.;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N;.;D;D;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.92	T;.;T;T;T;.
Sift4G	Uncertain	0.060	T;.;T;T;T;.
Polyphen		0.20	B;B;.;.;.;B
Vest4		0.56
MutPred		0.94		Gain of MoRF binding (P = 0.0597);Gain of MoRF binding (P = 0.0597);Gain of MoRF binding (P = 0.0597);Gain of MoRF binding (P = 0.0597);Gain of MoRF binding (P = 0.0597);Gain of MoRF binding (P = 0.0597);
MVP		0.85
MPC		2.2
ClinPred		0.053	T
GERP RS		3.6
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs9378251; hg19: chr6-32006291; COSMIC: COSV100926680; COSMIC: COSV100926680;