rs6474

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000500.9(CYP21A2):c.308G>A(p.Arg103Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,595,216 control chromosomes in the GnomAD database, including 79,844 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 0.26 ( 6406 hom., cov: 30)

Exomes 𝑓: 0.31 ( 73438 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.600

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.930662E-4).

BP6

Variant 6-32039109-G-A is Benign according to our data. Variant chr6-32039109-G-A is described in ClinVar as [Benign]. Clinvar id is 65608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039109-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.308G>A	p.Arg103Lys	missense_variant	Exon 3 of 10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
CYP21A2	NM_001128590.4 link	c.218G>A	p.Arg73Lys	missense_variant	Exon 2 of 9		NP_001122062.3	P08686Q08AG9
CYP21A2	NM_001368143.2 link	c.-98G>A		5_prime_UTR_variant	Exon 3 of 10		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.-98G>A		5_prime_UTR_variant	Exon 2 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.308G>A	p.Arg103Lys	missense_variant	Exon 3 of 10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

38624

AN:

150542

Hom.:

6397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0587

Gnomad AMI

AF:

0.477

Gnomad AMR

AF:

0.373

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.206

Gnomad SAS

AF:

0.229

Gnomad FIN

AF:

0.387

Gnomad MID

AF:

0.340

Gnomad NFE

AF:

0.323

Gnomad OTH

AF:

0.254

GnomAD3 exomes

AF:

0.316

AC:

75713

AN:

239240

Hom.:

13678

AF XY:

0.314

AC XY:

40568

AN XY:

129016

show subpopulations

Gnomad AFR exome

AF:

0.0484

Gnomad AMR exome

AF:

0.448

Gnomad ASJ exome

AF:

0.458

Gnomad EAS exome

AF:

0.190

Gnomad SAS exome

AF:

0.231

Gnomad FIN exome

AF:

0.380

Gnomad NFE exome

AF:

0.333

Gnomad OTH exome

AF:

0.319

GnomAD4 exome

AF:

0.310

AC:

447411

AN:

1444554

Hom.:

73438

Cov.:

AF XY:

0.310

AC XY:

222057

AN XY:

717456

show subpopulations

Gnomad4 AFR exome

AF:

0.0499

Gnomad4 AMR exome

AF:

0.440

Gnomad4 ASJ exome

AF:

0.450

Gnomad4 EAS exome

AF:

0.269

Gnomad4 SAS exome

AF:

0.236

Gnomad4 FIN exome

AF:

0.380

Gnomad4 NFE exome

AF:

0.314

Gnomad4 OTH exome

AF:

0.293

GnomAD4 genome

AF:

0.256

AC:

38642

AN:

150662

Hom.:

6406

Cov.:

AF XY:

0.261

AC XY:

19189

AN XY:

73518

show subpopulations

Gnomad4 AFR

AF:

0.0585

Gnomad4 AMR

AF:

0.374

Gnomad4 ASJ

AF:

0.457

Gnomad4 EAS

AF:

0.206

Gnomad4 SAS

AF:

0.229

Gnomad4 FIN

AF:

0.387

Gnomad4 NFE

AF:

0.323

Gnomad4 OTH

AF:

0.256

Alfa

AF:

0.271

Hom.:

3224

Bravo

AF:

0.248

TwinsUK

AF:

0.317

AC:

1176

ALSPAC

AF:

0.307

AC:

1183

ESP6500AA

AF:

0.0693

AC:

305

ESP6500EA

AF:

0.315

AC:

2705

ExAC

AF:

0.300

AC:

36377

Asia WGS

AF:

0.221

AC:

769

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1Other:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jul 18, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.090

DANN

Benign

0.63

DEOGEN2

Benign

0.0063

.;.;.;T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.055

.;.;T;T;.;.

MetaRNN

Benign

0.00059

T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.86

N;.;N;N;N;.

REVEL

Benign

0.068

Sift

Benign

0.49

T;.;T;T;T;.

Sift4G

Benign

1.0

T;.;T;T;T;.

Polyphen

0.0

B;B;.;.;.;B

Vest4

0.024

MPC

0.47

ClinPred

0.0043

GERP RS

-4.4

gMVP

0.30

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