Variant rs368330593 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000500.9(CYP21A2):c.227G>A(p.Arg76Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,418,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 28)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.448

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0044460595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CYP21A2	NM_000500.9 linkuse as main transcript	c.227G>A	p.Arg76Lys	missense_variant	2/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001368143.2 linkuse as main transcript	c.-198G>A		5_prime_UTR_variant	2/10		NP_001355072.1
CYP21A2	NM_001128590.4 linkuse as main transcript	c.202+122G>A		intron_variant			NP_001122062.3
CYP21A2	NM_001368144.2 linkuse as main transcript	c.-133+122G>A		intron_variant			NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.227G>A	p.Arg76Lys	missense_variant	2/10		NM_000500.9	ENSP00000496625	P1

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

170

AN:

151686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00395

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

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:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000194

AC:

AN:

180472

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

97338

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.000110

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

148

AN:

1266810

Hom.:

Cov.:

AF XY:

0.0000867

AC XY:

AN XY:

634612

show subpopulations

Gnomad4 AFR exome

AF:

0.00422

Gnomad4 AMR exome

AF:

0.000157

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:

0.00000633

Gnomad4 OTH exome

AF:

0.000185

GnomAD4 genome

AF:

0.00112

AC:

170

AN:

151804

Hom.:

Cov.:

AF XY:

0.000849

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00394

Gnomad4 AMR

AF:

0.000329

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000513

Hom.:

Bravo

AF:

0.00125

ESP6500AA

AF:

0.00263

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000261

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0025

.;.;.;T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.67

.;.;T;T;.

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.0044

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.14

N;.;N;N;.

REVEL

Benign

0.078

Sift

Benign

0.61

T;.;T;T;.

Sift4G

Benign

0.73

T;.;T;T;.

Polyphen

0.0090

B;B;.;.;B

Vest4

0.074

MVP

0.91

MPC

2.0

ClinPred

0.0031

GERP RS

1.1

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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