rs6474

Variant names:

• chr6-32039109-G-A
• rs6474
• NM_000500.9:c.308G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32039109-G-A
• chr6-32039109-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000500.9(CYP21A2):​c.308G>A​(p.Arg103Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,595,216 control chromosomes in the GnomAD database, including 79,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6406 hom., cov: 30)
  • Exomes 𝑓: 0.31 (73438 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.600
• Publications: 47 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 -19 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=5.930662E-4).
• BP6: Variant 6-32039109-G-A is Benign according to our data. Variant chr6-32039109-G-A is described in ClinVar as Benign. ClinVar VariationId is 65608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

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.308G>A	p.Arg103Lys	missense	Exon 3 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.218G>A	p.Arg73Lys	missense	Exon 2 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-98G>A		5_prime_UTR	Exon 3 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.308G>A	p.Arg103Lys	missense	Exon 3 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.308G>A	p.Arg103Lys	missense	Exon 3 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.308G>A	p.Arg103Lys	missense	Exon 3 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38624 AN: 150542 Hom.: 6397 Cov.: 30

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.316 AC: 75713 AN: 239240 AF XY: 0.314

Gnomad AFR exome AF: 0.0484

Gnomad AMR exome AF: 0.448

Gnomad ASJ exome AF: 0.458

Gnomad EAS exome AF: 0.190

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.310 AC: 447411 AN: 1444554 Hom.: 73438 Cov.: 83 AF XY: 0.310 AC XY: 222057 AN XY: 717456

African (AFR) AF: 0.0499 AC: 1644 AN: 32944

American (AMR) AF: 0.440 AC: 19211 AN: 43710

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 11598 AN: 25768

East Asian (EAS) AF: 0.269 AC: 10400 AN: 38710

South Asian (SAS) AF: 0.236 AC: 19937 AN: 84618

European-Finnish (FIN) AF: 0.380 AC: 19713 AN: 51876

Middle Eastern (MID) AF: 0.320 AC: 1780 AN: 5558

European-Non Finnish (NFE) AF: 0.314 AC: 345721 AN: 1101976

Other (OTH) AF: 0.293 AC: 17407 AN: 59394

GnomAD4 genome AF: 0.256 AC: 38642 AN: 150662 Hom.: 6406 Cov.: 30 AF XY: 0.261 AC XY: 19189 AN XY: 73518

African (AFR) AF: 0.0585 AC: 2408 AN: 41156

American (AMR) AF: 0.374 AC: 5673 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1578 AN: 3450

East Asian (EAS) AF: 0.206 AC: 1033 AN: 5018

South Asian (SAS) AF: 0.229 AC: 1077 AN: 4696

European-Finnish (FIN) AF: 0.387 AC: 3988 AN: 10298

Middle Eastern (MID) AF: 0.352 AC: 102 AN: 290

European-Non Finnish (NFE) AF: 0.323 AC: 21819 AN: 67584

Other (OTH) AF: 0.256 AC: 534 AN: 2090

Alfa AF: 0.275 Hom.: 4400

Bravo AF: 0.248

TwinsUK AF: 0.317 AC: 1176

ALSPAC AF: 0.307 AC: 1183

ESP6500AA AF: 0.0693 AC: 305

ESP6500EA AF: 0.315 AC: 2705

ExAC AF: 0.300 AC: 36377

Asia WGS AF: 0.221 AC: 769 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.090
DANN	Benign	0.63
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.055	T
MetaRNN	Benign	0.00059	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.60
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.068
Sift	Benign	0.49	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.47
ClinPred		0.0043	T
GERP RS		-4.4
gMVP		0.30
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6474; hg19: chr6-32006886; COSMIC: COSV64476105; COSMIC: COSV64476105;