rs368330593

Variant names:

• chr6-32038746-G-A
• rs368330593
• NM_000500.9:c.227G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_000500.9(CYP21A2):​c.227G>A​(p.Arg76Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,418,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 28)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.448
• Publications: 1 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), Myriad Women’s Health, Laboratory for Molecular Medicine
• 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: Likely_benign. The variant received -3 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=0.0044460595).

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.227G>A	p.Arg76Lys	missense	Exon 2 of 10	NP_000491.4
	CYP21A2	NM_001368143.2		c.-198G>A		5_prime_UTR	Exon 2 of 10	NP_001355072.1
	CYP21A2	NM_001128590.4		c.202+122G>A		intron	N/A	NP_001122062.3	P08686-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.227G>A	p.Arg76Lys	missense	Exon 2 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.227G>A	p.Arg76Lys	missense	Exon 2 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.227G>A	p.Arg76Lys	missense	Exon 2 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 151686 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.00395

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000194 AC: 35 AN: 180472 AF XY: 0.000113

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.000117 AC: 148 AN: 1266810 Hom.: 0 Cov.: 20 AF XY: 0.0000867 AC XY: 55 AN XY: 634612

African (AFR) AF: 0.00422 AC: 126 AN: 29852

American (AMR) AF: 0.000157 AC: 6 AN: 38294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24378

East Asian (EAS) AF: 0.00 AC: 0 AN: 37670

South Asian (SAS) AF: 0.00 AC: 0 AN: 79526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.00000633 AC: 6 AN: 947618

Other (OTH) AF: 0.000185 AC: 10 AN: 53964

GnomAD4 genome AF: 0.00112 AC: 170 AN: 151804 Hom.: 1 Cov.: 28 AF XY: 0.000849 AC XY: 63 AN XY: 74178

African (AFR) AF: 0.00394 AC: 163 AN: 41388

American (AMR) AF: 0.000329 AC: 5 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67926

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000513 Hom.: 0

Bravo AF: 0.00125

ESP6500AA AF: 0.00263 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000261 AC: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.45
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.078
Sift	Benign	0.61	T
Sift4G	Benign	0.73	T
Polyphen		0.0090	B
Vest4		0.074
MVP		0.91
MPC		2.0
ClinPred		0.0031	T
GERP RS		1.1
PromoterAI		0.015	Neutral
gMVP		0.39
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs368330593; hg19: chr6-32006523;