Variant chr6-32038482-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000500.9(CYP21A2):c.60G>C(p.Trp20Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,587,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

Variant links:

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 links:

CYP21A2 (HGNC:):

CYP21A2 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.60G>C	p.Trp20Cys	missense_variant	1/10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
CYP21A2	NM_001128590.4 linkuse as main transcript	c.60G>C	p.Trp20Cys	missense_variant	1/9		NP_001122062.3	P08686Q08AG9
CYP21A2	NM_001368143.2 linkuse as main transcript	c.-365G>C		5_prime_UTR_variant	1/10		NP_001355072.1
CYP21A2	NM_001368144.2 linkuse as main transcript	c.-275G>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 linkuse as main transcript	c.60G>C	p.Trp20Cys	missense_variant	1/10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

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

GnomAD3 exomes

AF:

0.0000980

AC:

AN:

204022

Hom.:

AF XY:

0.0000718

AC XY:

AN XY:

111458

show subpopulations

Gnomad AFR exome

AF:

0.000450

Gnomad AMR exome

AF:

0.000430

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000232

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000293

AC:

AN:

1435034

Hom.:

Cov.:

104

AF XY:

0.0000281

AC XY:

AN XY:

711674

show subpopulations

Gnomad4 AFR exome

AF:

0.000519

Gnomad4 AMR exome

AF:

0.000440

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000546

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.000164

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.000603

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000174

ExAC

AF:

0.0000415

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

.;.;.;T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.76

.;.;T;T;.;.

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.47

T;T;T;T;T;T

MetaSVM

Benign

-0.45

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.3

D;.;D;D;D;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;.;D;D;D;.

Sift4G

Uncertain

0.0030

D;.;D;D;D;.

Polyphen

1.0

D;D;.;.;.;D

Vest4

0.47

MutPred

0.60

Loss of catalytic residue at L18 (P = 0.0039);Loss of catalytic residue at L18 (P = 0.0039);Loss of catalytic residue at L18 (P = 0.0039);Loss of catalytic residue at L18 (P = 0.0039);Loss of catalytic residue at L18 (P = 0.0039);Loss of catalytic residue at L18 (P = 0.0039);

MVP

0.90

MPC

4.9

ClinPred

0.39

GERP RS

4.5

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over