Variant 6-32038491-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000500.9(CYP21A2):c.69G>T(p.Trp23Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,591,562 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00046 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 1 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04066196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP21A2	NM_000500.9 linkuse as main transcript	c.69G>T	p.Trp23Cys	missense_variant	1/10	ENST00000644719.2
CYP21A2	NM_001128590.4 linkuse as main transcript	c.69G>T	p.Trp23Cys	missense_variant	1/9
CYP21A2	NM_001368143.2 linkuse as main transcript	c.-356G>T		5_prime_UTR_variant	1/10
CYP21A2	NM_001368144.2 linkuse as main transcript	c.-266G>T		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.69G>T	p.Trp23Cys	missense_variant	1/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.000765

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000546

AC:

115

AN:

210526

Hom.:

AF XY:

0.000584

AC XY:

AN XY:

114778

show subpopulations

Gnomad AFR exome

AF:

0.000167

Gnomad AMR exome

AF:

0.000744

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:

0.000968

Gnomad OTH exome

AF:

0.000559

GnomAD4 exome

AF:

0.000514

AC:

740

AN:

1439350

Hom.:

Cov.:

104

AF XY:

0.000522

AC XY:

373

AN XY:

714210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000609

Gnomad4 AMR exome

AF:

0.000601

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000197

Gnomad4 NFE exome

AF:

0.000623

Gnomad4 OTH exome

AF:

0.000437

GnomAD4 genome

AF:

0.000460

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000765

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000457

ExAC

AF:

0.000356

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.10

.;.;.;T;.;.

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.90

.;.;D;D;.;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.041

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.4

D;.;D;D;D;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

D;.;D;D;D;.

Sift4G

Benign

0.087

T;.;D;D;T;.

Polyphen

1.0

D;D;.;.;.;D

Vest4

0.45

MutPred

0.61

Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);

MVP

0.81

MPC

4.9

ClinPred

0.082

GERP RS

3.6

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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