6-32038511-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000500.9(CYP21A2):​c.89T>C​(p.Leu30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.89T>C	p.Leu30Pro	missense_variant	Exon 1 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.89T>C	p.Leu30Pro	missense_variant	Exon 1 of 9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-336T>C		5_prime_UTR_variant	Exon 1 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-246T>C		5_prime_UTR_variant	Exon 1 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.89T>C	p.Leu30Pro	missense_variant	Exon 1 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 104

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89T>C (p.L30P) alteration is located in exon 1 (coding exon 1) of the CYP21A2 gene. This alteration results from a T to C substitution at nucleotide position 89, causing the leucine (L) at amino acid position 30 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	.;.;.;T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.88	.;.;D;D;.;.
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;.;N;N;N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.011	D;.;D;D;D;.
Sift4G	Benign	0.10	T;.;D;D;T;.
Polyphen		1.0	D;D;.;.;.;D
Vest4		0.53
MutPred		0.56		Gain of glycosylation at L30 (P = 0.0175);Gain of glycosylation at L30 (P = 0.0175);Gain of glycosylation at L30 (P = 0.0175);Gain of glycosylation at L30 (P = 0.0175);Gain of glycosylation at L30 (P = 0.0175);Gain of glycosylation at L30 (P = 0.0175);
MVP		0.96
MPC		5.0
ClinPred		0.68	D
GERP RS		4.5
gMVP		0.66

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-32006288;