rs1554299737

Positions:

• chr6-32039807-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000500.9(CYP21A2):​c.710T>A​(p.Ile237Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.20

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 22) in uniprot entity CP21A_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000500.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 6-32039807-T-A is Pathogenic according to our data. Variant chr6-32039807-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039807-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.710T>A	p.Ile237Asn	missense_variant	6/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.620T>A	p.Ile207Asn	missense_variant	5/9		NP_001122062.3
CYP21A2	NM_001368143.2	c.305T>A	p.Ile102Asn	missense_variant	6/10		NP_001355072.1
CYP21A2	NM_001368144.2	c.305T>A	p.Ile102Asn	missense_variant	5/9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.710T>A	p.Ile237Asn	missense_variant	6/10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461700 Hom.: 0 Cov.: 61 AF XY: 0.00 AC XY: 0 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74436

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces isoleucine with asparagine at codon 237 of the CYP21A2 protein (p.Ile237Asn). 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. The c.710T>A (p.Ile237Asn) variant alone has not been reported in the literature in individuals with CYP21A2-related conditions. However, it has been reported to co-occur with the c.713T>A (p.Val238Glu) and c.719T>A (p.Met240Lys) variants in cis (on the same chromosome), which is known as the c.[710T>A;713T>A;719T>A] haplotype, E6 cluster, or CL6. This haplotype has been reported in the literature as homozygous or in combination with other CYP21A2 variants in individual(s) affected with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 12915679, 1644925, 23359698, 26804566). ClinVar contains an entry for this variant (Variation ID: 242761). 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. The c.710T>A (p.Ile237Asn) variant alone affects CYP21A2 protein function, and the c.[710T>A;713T>A;719T>A] haplotype has been reported to abolish enzyme activity (PMID: 15623806). For these reasons, this variant on the c.[710T>A;713T>A;719T>A] haplotype has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2017	The CYP21A2 c.710T>A (p.Ile237Asn) pathogenic variant (also known as I236N) is usually associated with the simple virilizing form of congenital adrenal hyperplasia. The variant has been found in at least one symptomatic individual. Functional evidence suggests that this variant may impact protein function. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 16, 2014	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 1869518, 2249999, 28161392, 31333583). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 28161392). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 10, 2024	PM1, PM2, PM5, PP3, PP5 -

Congenital adrenal hyperplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 21, 2022

Variant summary: CYP21A2 c.710T>A (p.Ile237Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 150898 control chromosomes (gnomAD v3.1.2). p.I237N is found to be part of a recurrent cluster of 3 variants (I237N, V238E and M240K), which belongs to a group of common, pseudogene-derived mutations that are found in patients with classical CAH. This cluster of 3 variants is assumed to be transferred together from the CYP21A1P pseudogene to CYP21A2 in a continuous stretch of DNA (Robins_2005). To our knowledge, p.I237N has been reported in the literature as part of this cluster of 3 variants or in combination with only p.V238E in individuals affected with Congenital Adrenal Hyperplasia (e.g. Higashi_1991, Barbat_1995, Lee_2006, Chang_2011, Kirac_2014, Essawi_2020, Wang_2021). These reports do not provide unequivocal conclusions about association of the p.I237N variant alone with Congenital Adrenal Hyperplasia. Nevertheless, experimental evidence evaluating an impact on protein function demonstrated that the p.I237N variant alone causes a severely reduced enzyme activity (Robins_2005). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	-0.038
FATHMM_MKL	Benign	0.13	N
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.066	T
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.0	D;.;D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Uncertain	0.019	D;.;D;.
Polyphen		0.84	P;P;.;P
Vest4		0.49
MutPred		0.92		Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);.;Gain of disorder (P = 0.0085);
MVP		0.96
MPC		1.7
ClinPred		0.85	D
GERP RS		4.1
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554299737; hg19: chr6-32007584;