rs9378252

Positions:

• chr6-32038610-A-C
• chr6-32038610-A-G
• chr6-32038610-A-T

Variant summary

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

The NM_000500.9(CYP21A2):​c.188A>C​(p.His63Pro) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H63L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 28)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.135

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/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.188A>C	p.His63Pro	missense_variant	1/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.188A>C	p.His63Pro	missense_variant	1/9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-237A>C		5_prime_UTR_variant	1/10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-147A>C		5_prime_UTR_variant	1/9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.188A>C	p.His63Pro	missense_variant	1/10		NM_000500.9	ENSP00000496625	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Benign	0.81
DEOGEN2	Benign	0.067	.;.;.;T;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.79	.;.;T;T;.;.
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.5	N;.;D;D;N;.
REVEL	Uncertain	0.51
Sift	Benign	0.11	T;.;T;D;T;.
Sift4G	Uncertain	0.030	D;.;D;D;D;.
Polyphen		0.77	P;P;.;.;.;P
Vest4		0.30
MutPred		0.81		Loss of methylation at R61 (P = 0.0817);Loss of methylation at R61 (P = 0.0817);Loss of methylation at R61 (P = 0.0817);Loss of methylation at R61 (P = 0.0817);Loss of methylation at R61 (P = 0.0817);Loss of methylation at R61 (P = 0.0817);
MVP		0.98
MPC		3.5
ClinPred		0.29	T
GERP RS		-1.8
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9378252; hg19: chr6-32006387;