rs202242769

Variant names:

• chr6-32040723-G-A
• rs202242769
• NM_000500.9:c.1174G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32040723-G-A
• chr6-32040723-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_000500.9(CYP21A2):​c.1174G>A​(p.Ala392Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,547,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:6
• Conservation: PhyloP100: 2.31
• Publications: 19 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0271) population. However there is too low homozygotes in high coverage region: (expected more than 19, got 0).
• 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.
• PP5: Variant 6-32040723-G-A is Pathogenic according to our data. Variant chr6-32040723-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225335.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0167332). . Strength limited to SUPPORTING due to the PP5.

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.1174G>A	p.Ala392Thr	missense	Exon 9 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.1084G>A	p.Ala362Thr	missense	Exon 8 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.769G>A	p.Ala257Thr	missense	Exon 9 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.1174G>A	p.Ala392Thr	missense	Exon 9 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.1210G>A	p.Ala404Thr	missense	Exon 9 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.1183G>A	p.Ala395Thr	missense	Exon 9 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 852 AN: 151502 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00519

Gnomad ASJ AF: 0.00636

Gnomad EAS AF: 0.00759

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00463

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00678

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00921 AC: 2164 AN: 234892 AF XY: 0.0103

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00739

Gnomad EAS exome AF: 0.00809

Gnomad FIN exome AF: 0.00535

Gnomad NFE exome AF: 0.00797

Gnomad OTH exome AF: 0.00611

GnomAD4 exome AF: 0.00733 AC: 10227 AN: 1395894 Hom.: 0 Cov.: 31 AF XY: 0.00812 AC XY: 5661 AN XY: 697232

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

African (AFR) AF: 0.00143 AC: 47 AN: 32970

American (AMR) AF: 0.00294 AC: 131 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00618 AC: 159 AN: 25742

East Asian (EAS) AF: 0.00522 AC: 205 AN: 39308

South Asian (SAS) AF: 0.0281 AC: 2346 AN: 83614

European-Finnish (FIN) AF: 0.00571 AC: 301 AN: 52708

Middle Eastern (MID) AF: 0.00777 AC: 44 AN: 5664

European-Non Finnish (NFE) AF: 0.00620 AC: 6531 AN: 1053192

Other (OTH) AF: 0.00796 AC: 463 AN: 58152

⚠️ 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: 0.00562 AC: 852 AN: 151616 Hom.: 0 Cov.: 33 AF XY: 0.00610 AC XY: 452 AN XY: 74074

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

African (AFR) AF: 0.00193 AC: 80 AN: 41514

American (AMR) AF: 0.00518 AC: 79 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00636 AC: 22 AN: 3458

East Asian (EAS) AF: 0.00761 AC: 39 AN: 5126

South Asian (SAS) AF: 0.0236 AC: 111 AN: 4698

European-Finnish (FIN) AF: 0.00463 AC: 49 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00680 AC: 460 AN: 67674

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

⚠️ 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: 0.00497 Hom.: 0

ExAC AF: 0.0109 AC: 1321

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	3	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (8)
5	2	-	not provided (7)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.45	T
PhyloP100		2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.39
Sift	Benign	0.22	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.21
MPC		2.9
ClinPred		0.96	D
GERP RS		3.9
gMVP		0.82
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs202242769; hg19: chr6-32008500; COSMIC: COSV64479600; COSMIC: COSV64479600;