6-32039548-C-G

Variant names:

• chr6-32039548-C-G
• rs397515531
• NM_000500.9:c.552C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 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. 16/20 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:5 O:1
• Conservation: PhyloP100: -0.725
• Publications: 9 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Myriad Women’s Health
• 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: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.
• 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 Benign/Likely_benign. ClinVar VariationId is 65609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000500.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.552C>G	p.Asp184Glu	missense splice_region	Exon 5 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.462C>G	p.Asp154Glu	missense splice_region	Exon 4 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.147C>G	p.Asp49Glu	missense splice_region	Exon 5 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.552C>G	p.Asp184Glu	missense splice_region	Exon 5 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.552C>G	p.Asp184Glu	missense splice_region	Exon 5 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.552C>G	p.Asp184Glu	missense splice_region	Exon 5 of 10	ENSP00000630656.1

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

GnomAD2 exomes AF: 0.00145 AC: 308 AN: 211870 AF XY: 0.00136

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 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

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

African (AFR) AF: 0.000852 AC: 28 AN: 32878

American (AMR) AF: 0.00487 AC: 192 AN: 39452

Ashkenazi Jewish (ASJ) AF: 0.000350 AC: 9 AN: 25710

East Asian (EAS) AF: 0.000755 AC: 29 AN: 38394

South Asian (SAS) AF: 0.00160 AC: 133 AN: 83138

European-Finnish (FIN) AF: 0.00658 AC: 336 AN: 51100

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5722

European-Non Finnish (NFE) AF: 0.00178 AC: 1946 AN: 1094542

Other (OTH) AF: 0.00230 AC: 136 AN: 59078

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

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

African (AFR) AF: 0.00109 AC: 45 AN: 41318

American (AMR) AF: 0.00697 AC: 103 AN: 14772

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000979 AC: 5 AN: 5106

South Asian (SAS) AF: 0.00230 AC: 11 AN: 4784

European-Finnish (FIN) AF: 0.00800 AC: 83 AN: 10378

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00292 AC: 198 AN: 67818

Other (OTH) AF: 0.00337 AC: 7 AN: 2076

⚠️ 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: 0.00123 Hom.: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000588 AC: 71

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
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
MetaSVM	Benign	-1.1	T
PhyloP100		-0.72
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.034
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.069
MutPred		0.44		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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs397515531; hg19: chr6-32007325; COSMIC: COSV100926711; COSMIC: COSV100926711;