chr6-32038511-T-A

Variant names:

• chr6-32038511-T-A
• rs1303387085
• NM_000500.9:c.89T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000500.9(CYP21A2):​c.89T>A​(p.Leu30His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L30P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.80
• Publications: 0 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 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000500.9
• PM2: Very rare variant in population databases, with high coverage
• 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.

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.89T>A	p.Leu30His	missense	Exon 1 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.89T>A	p.Leu30His	missense	Exon 1 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-336T>A		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.89T>A	p.Leu30His	missense	Exon 1 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.89T>A	p.Leu30His	missense	Exon 1 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.89T>A	p.Leu30His	missense	Exon 1 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151998 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 237104 AF XY: 0.00000776

Gnomad AFR exome AF: 0.0000685

Gnomad AMR exome AF: 0.00

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: 0.00000138 AC: 2 AN: 1454356 Hom.: 0 Cov.: 104 AF XY: 0.00000138 AC XY: 1 AN XY: 722858

African (AFR) AF: 0.0000300 AC: 1 AN: 33284

American (AMR) AF: 0.0000228 AC: 1 AN: 43828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39490

South Asian (SAS) AF: 0.00 AC: 0 AN: 85320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108298

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74258

African (AFR) AF: 0.0000725 AC: 3 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.49	T
PhyloP100		2.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.017	D
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.49
MutPred		0.53		Gain of disorder (P = 0.0264)
MVP		0.98
MPC		4.3
ClinPred		0.38	T
GERP RS		4.5
PromoterAI		0.025	Neutral
gMVP		0.53
Mutation Taster		=53/47	polymorphism

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: rs1303387085; hg19: chr6-32006288;