rs9378251

Positions:

• chr6-32038514-C-A
• chr6-32038514-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000500.9(CYP21A2):​c.92C>A​(p.Pro31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.34

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-32038514-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 6-32038514-C-A is Pathogenic according to our data. Variant chr6-32038514-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 988330.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.92C>A	p.Pro31Gln	missense_variant	1/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.92C>A	p.Pro31Gln	missense_variant	1/9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-333C>A		5_prime_UTR_variant	1/10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-243C>A		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.92C>A	p.Pro31Gln	missense_variant	1/10		NM_000500.9	ENSP00000496625	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 107

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Nov 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;.;.;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.89	.;.;D;D;.;.
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.066	D
MutationTaster	Benign	0.56	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D;.;D;D;D;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.024	D;.;D;D;D;.
Sift4G	Uncertain	0.0040	D;.;D;D;D;.
Polyphen		1.0	D;D;.;.;.;D
Vest4		0.85
MutPred		0.94		Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);
MVP		0.93
MPC		3.3
ClinPred		0.95	D
GERP RS		3.6
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs9378251; hg19: chr6-32006291;