6-32040072-G-C

Position:

chr6-32040072-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000500.9(CYP21A2):c.806G>C(p.Ser269Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,536,460 control chromosomes in the GnomAD database, including 9,528 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1536 hom., cov: 32)

Exomes 𝑓: 0.11 ( 7992 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:2

Conservation

PhyloP100: -0.979

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013784409).

BP6

Variant 6-32040072-G-C is Benign according to our data. Variant chr6-32040072-G-C is described in ClinVar as [Benign]. Clinvar id is 12154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32040072-G-C is described in Lovd as [Likely_benign]. Variant chr6-32040072-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9 linkuse as main transcript	c.806G>C	p.Ser269Thr	missense_variant	7/10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
CYP21A2	NM_001128590.4 linkuse as main transcript	c.716G>C	p.Ser239Thr	missense_variant	6/9		NP_001122062.3	P08686Q08AG9
CYP21A2	NM_001368143.2 linkuse as main transcript	c.401G>C	p.Ser134Thr	missense_variant	7/10		NP_001355072.1
CYP21A2	NM_001368144.2 linkuse as main transcript	c.401G>C	p.Ser134Thr	missense_variant	6/9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.806G>C	p.Ser269Thr	missense_variant	7/10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20079

AN:

149138

Hom.:

1530

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.0166

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0992

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.0620

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.0939

Gnomad OTH

AF:

0.166

GnomAD3 exomes

AF:

0.129

AC:

30937

AN:

238976

Hom.:

2086

AF XY:

0.136

AC XY:

17645

AN XY:

130202

show subpopulations

Gnomad AFR exome

AF:

0.252

Gnomad AMR exome

AF:

0.0932

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.105

Gnomad SAS exome

AF:

0.253

Gnomad FIN exome

AF:

0.0668

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.109

AC:

151700

AN:

1387202

Hom.:

7992

Cov.:

AF XY:

0.113

AC XY:

78540

AN XY:

692024

show subpopulations

Gnomad4 AFR exome

AF:

0.248

Gnomad4 AMR exome

AF:

0.0969

Gnomad4 ASJ exome

AF:

0.103

Gnomad4 EAS exome

AF:

0.106

Gnomad4 SAS exome

AF:

0.246

Gnomad4 FIN exome

AF:

0.0687

Gnomad4 NFE exome

AF:

0.0958

Gnomad4 OTH exome

AF:

0.121

GnomAD4 genome

AF:

0.135

AC:

20106

AN:

149258

Hom.:

1536

Cov.:

AF XY:

0.137

AC XY:

9981

AN XY:

73048

show subpopulations

Gnomad4 AFR

AF:

0.220

Gnomad4 AMR

AF:

0.135

Gnomad4 ASJ

AF:

0.106

Gnomad4 EAS

AF:

0.0995

Gnomad4 SAS

AF:

0.215

Gnomad4 FIN

AF:

0.0620

Gnomad4 NFE

AF:

0.0939

Gnomad4 OTH

AF:

0.164

Alfa

AF:

0.0734

Hom.:

Bravo

AF:

0.142

ESP6500AA

AF:

0.219

AC:

662

ESP6500EA

AF:

0.0978

AC:

530

ExAC

AF:

0.151

AC:

18188

Asia WGS

AF:

0.231

AC:

804

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

21-HYDROXYLASE POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Aug 01, 1991

- -

Congenital adrenal hyperplasia

Other:1

not provided, no classification provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.15

DANN

Benign

0.66

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.050

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

N;.;N;.

REVEL

Benign

0.064

Sift

Benign

0.33

T;.;T;.

Sift4G

Benign

0.60

T;.;T;.

Polyphen

0.022

B;B;.;B

Vest4

0.041

MPC

0.43

ClinPred

0.0022

GERP RS

-3.0

gMVP

0.22

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