rs201552310

chr6-32040140-G-Achr6-32040140-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000500.9(CYP21A2):c.874G>A(p.Gly292Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,734 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G292R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.99

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 18 ACMG points.

• PM1: In a helix (size 31) in uniprot entity CP21A_HUMAN there are 24 pathogenic changes around while only 1 benign (96%) in NM_000500.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-32040140-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1498831.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 6-32040140-G-A is Pathogenic according to our data. Variant chr6-32040140-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12156.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.874G>A	p.Gly292Ser	missense_variant	7/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.784G>A	p.Gly262Ser	missense_variant	6/9
CYP21A2	NM_001368143.2	c.469G>A	p.Gly157Ser	missense_variant	7/10
CYP21A2	NM_001368144.2	c.469G>A	p.Gly157Ser	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.874G>A	p.Gly292Ser	missense_variant	7/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246550 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460542 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726596

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 03, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 29, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 292 of the CYP21A2 protein (p.Gly292Ser). 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 salt-wasting and simple virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 9497336, 26206692, 34821488). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12156). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 9497336, 28539365). This variant disrupts the p.Gly292 amino acid residue in CYP21A2. Other variant(s) that disrupt this residue have been observed in individuals with CYP21A2-related conditions (PMID: 10364682, 12915679), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.6	D;.;N;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0080	D;.;D;.
Sift4G	Uncertain	0.012	D;.;D;.
Polyphen		1.0	D;D;.;D
Vest4		0.93
MutPred		0.90		Gain of glycosylation at G292 (P = 0.013);Gain of glycosylation at G292 (P = 0.013);.;Gain of glycosylation at G292 (P = 0.013);
MVP		0.97
MPC		1.3
ClinPred		0.98	D
GERP RS		5.0
gMVP		0.74

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: rs201552310; hg19: chr6-32007917; COSMIC: COSV64475788; COSMIC: COSV64475788;