rs267606757

Positions:

• chr6-32039162-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_Moderate PM2 PP3_Moderate

The NM_000500.9(CYP21A2):​c.361A>C​(p.Lys121Gln) 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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.27

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_000500.9 (CYP21A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.361A>C	p.Lys121Gln	missense_variant	3/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.271A>C	p.Lys91Gln	missense_variant	2/9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-45A>C		5_prime_UTR_variant	3/10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-45A>C		5_prime_UTR_variant	2/9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.361A>C	p.Lys121Gln	missense_variant	3/10		NM_000500.9	ENSP00000496625	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 76

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	.;.;.;T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	.;.;D;D;.;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N;.;N;N;N;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0060	D;.;D;D;D;.
Sift4G	Uncertain	0.020	D;.;D;D;D;.
Polyphen		0.99	D;D;.;.;.;D
Vest4		0.54
MutPred		0.77		Loss of methylation at K121 (P = 0.0387);Loss of methylation at K121 (P = 0.0387);.;Loss of methylation at K121 (P = 0.0387);.;Loss of methylation at K121 (P = 0.0387);
MVP		0.88
MPC		1.4
ClinPred		0.88	D
GERP RS		4.6
gMVP		0.62

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: rs267606757; hg19: chr6-32006939;