6-32038610-A-T

Variant names:

• chr6-32038610-A-T
• rs9378252
• NM_000500.9:c.188A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_000500.9(CYP21A2):​c.188A>T​(p.His63Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00971 in 145,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0097 (0 hom., cov: 28)
  • Exomes 𝑓: 0.031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 B:2
• Conservation: PhyloP100: -0.135
• Publications: 26 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 -1 ACMG points.

• PM2: Variant has high frequency in the EAS (0.0441) population. However there is too low homozygotes in high coverage region: (expected more than 3, 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039593577).

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.188A>T	p.His63Leu	missense	Exon 1 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.188A>T	p.His63Leu	missense	Exon 1 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-237A>T		5_prime_UTR	Exon 1 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.188A>T	p.His63Leu	missense	Exon 1 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.188A>T	p.His63Leu	missense	Exon 1 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.188A>T	p.His63Leu	missense	Exon 1 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00970 AC: 1413 AN: 145720 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00211

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00351

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.00557

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0441 AC: 7165 AN: 162570 AF XY: 0.0426

Gnomad AFR exome AF: 0.00571

Gnomad AMR exome AF: 0.0632

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0366

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0310 AC: 43622 AN: 1406546 Hom.: 0 Cov.: 36 AF XY: 0.0304 AC XY: 21222 AN XY: 697948

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

African (AFR) AF: 0.00397 AC: 129 AN: 32494

American (AMR) AF: 0.0553 AC: 2230 AN: 40314

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 262 AN: 25476

East Asian (EAS) AF: 0.0918 AC: 3001 AN: 32688

South Asian (SAS) AF: 0.0208 AC: 1726 AN: 82864

European-Finnish (FIN) AF: 0.0319 AC: 1578 AN: 49424

Middle Eastern (MID) AF: 0.00802 AC: 45 AN: 5610

European-Non Finnish (NFE) AF: 0.0305 AC: 32942 AN: 1079968

Other (OTH) AF: 0.0296 AC: 1709 AN: 57708

⚠️ 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: 0.00971 AC: 1416 AN: 145832 Hom.: 0 Cov.: 28 AF XY: 0.0101 AC XY: 720 AN XY: 71284

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

African (AFR) AF: 0.00210 AC: 86 AN: 40874

American (AMR) AF: 0.0124 AC: 180 AN: 14528

Ashkenazi Jewish (ASJ) AF: 0.00351 AC: 12 AN: 3418

East Asian (EAS) AF: 0.0497 AC: 204 AN: 4104

South Asian (SAS) AF: 0.00578 AC: 27 AN: 4668

European-Finnish (FIN) AF: 0.0141 AC: 142 AN: 10090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0112 AC: 726 AN: 64924

Other (OTH) AF: 0.0138 AC: 28 AN: 2028

⚠️ 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: 0.0237 Hom.: 0

ExAC AF: 0.0300 AC: 3489

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	1	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (4)
2	-	-	not provided (2)
1	-	-	Congenital adrenal hyperplasia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.14
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.45
Sift	Benign	0.33	T
Sift4G	Uncertain	0.041	D
Polyphen		0.40	B
Vest4		0.12
MPC		2.3
ClinPred		0.0019	T
GERP RS		-1.8
PromoterAI		0.0022	Neutral
gMVP		0.60
Mutation Taster		=21/79	disease causing

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: rs9378252; hg19: chr6-32006387; COSMIC: COSV64473007; COSMIC: COSV64473007;