rs397515531

Positions:

• chr6-32039548-C-G
• chr6-32039548-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000500.9(CYP21A2):​c.552C>G​(p.Asp184Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,580,942 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (48 hom.)
• Consequence: CYP21A2 NM_000500.9 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.725

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0114969015).
• BP6: Variant 6-32039548-C-G is Benign according to our data. Variant chr6-32039548-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 65609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039548-C-G is described in Lovd as [Benign]. Variant chr6-32039548-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.552C>G	p.Asp184Glu	missense_variant, splice_region_variant	5/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.462C>G	p.Asp154Glu	missense_variant, splice_region_variant	4/9
CYP21A2	NM_001368143.2	c.147C>G	p.Asp49Glu	missense_variant, splice_region_variant	5/10
CYP21A2	NM_001368144.2	c.147C>G	p.Asp49Glu	missense_variant, splice_region_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.552C>G	p.Asp184Glu	missense_variant, splice_region_variant	5/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 453 AN: 150816 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00691

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000977

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.00341

GnomAD3 exomes AF: 0.00145 AC: 308 AN: 211870 Hom.: 12 AF XY: 0.00136 AC XY: 155 AN XY: 113944

Gnomad AFR exome AF: 0.000764

Gnomad AMR exome AF: 0.00392

Gnomad ASJ exome AF: 0.000214

Gnomad EAS exome AF: 0.000379

Gnomad SAS exome AF: 0.000769

Gnomad FIN exome AF: 0.00110

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00197 AC: 2812 AN: 1430014 Hom.: 48 Cov.: 58 AF XY: 0.00200 AC XY: 1419 AN XY: 708910

Gnomad4 AFR exome AF: 0.000852

Gnomad4 AMR exome AF: 0.00487

Gnomad4 ASJ exome AF: 0.000350

Gnomad4 EAS exome AF: 0.000755

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00658

Gnomad4 NFE exome AF: 0.00178

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00301 AC: 455 AN: 150928 Hom.: 2 Cov.: 31 AF XY: 0.00294 AC XY: 217 AN XY: 73740

Gnomad4 AFR AF: 0.00109

Gnomad4 AMR AF: 0.00697

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000979

Gnomad4 SAS AF: 0.00230

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.00292

Gnomad4 OTH AF: 0.00337

Alfa AF: 0.00123 Hom.: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000588 AC: 71

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CYP21A2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 05, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.5
DANN	Benign	0.76
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0022	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.21	N;.;N;.
REVEL	Benign	0.034
Sift	Benign	1.0	T;.;T;.
Sift4G	Benign	1.0	T;.;T;.
Polyphen		0.0010	B;B;.;B
Vest4		0.069
MutPred		0.44		Loss of ubiquitination at K183 (P = 0.0962);Loss of ubiquitination at K183 (P = 0.0962);.;Loss of ubiquitination at K183 (P = 0.0962);
MVP		0.39
MPC		0.43
ClinPred		0.000024	T
GERP RS		-3.4
gMVP		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs397515531; hg19: chr6-32007325; COSMIC: COSV100926711; COSMIC: COSV100926711;