chr6-32039548-C-G

Position:

chr6-32039548-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_000500.9(CYP21A2):c.552C>G(p.Asp184Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,580,942 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0020 ( 48 hom. )

Consequence

CYP21A2
NM_000500.9 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.725

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0114969015).

BP6

Variant 6-32039548-C-G is Benign according to our data. Variant chr6-32039548-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 65609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039548-C-G is described in Lovd as [Benign]. Variant chr6-32039548-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP21A2	NM_000500.9 linkuse as main transcript	c.552C>G	p.Asp184Glu	missense_variant, splice_region_variant	5/10	ENST00000644719.2
CYP21A2	NM_001128590.4 linkuse as main transcript	c.462C>G	p.Asp154Glu	missense_variant, splice_region_variant	4/9
CYP21A2	NM_001368143.2 linkuse as main transcript	c.147C>G	p.Asp49Glu	missense_variant, splice_region_variant	5/10
CYP21A2	NM_001368144.2 linkuse as main transcript	c.147C>G	p.Asp49Glu	missense_variant, splice_region_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.552C>G	p.Asp184Glu	missense_variant, splice_region_variant	5/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

453

AN:

150816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00691

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000977

Gnomad SAS

AF:

0.00230

Gnomad FIN

AF:

0.00800

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00292

Gnomad OTH

AF:

0.00341

GnomAD3 exomes

AF:

0.00145

AC:

308

AN:

211870

Hom.:

AF XY:

0.00136

AC XY:

155

AN XY:

113944

show subpopulations

Gnomad AFR exome

AF:

0.000764

Gnomad AMR exome

AF:

0.00392

Gnomad ASJ exome

AF:

0.000214

Gnomad EAS exome

AF:

0.000379

Gnomad SAS exome

AF:

0.000769

Gnomad FIN exome

AF:

0.00110

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00197

AC:

2812

AN:

1430014

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1419

AN XY:

708910

show subpopulations

Gnomad4 AFR exome

AF:

0.000852

Gnomad4 AMR exome

AF:

0.00487

Gnomad4 ASJ exome

AF:

0.000350

Gnomad4 EAS exome

AF:

0.000755

Gnomad4 SAS exome

AF:

0.00160

Gnomad4 FIN exome

AF:

0.00658

Gnomad4 NFE exome

AF:

0.00178

Gnomad4 OTH exome

AF:

0.00230

GnomAD4 genome

AF:

0.00301

AC:

455

AN:

150928

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

217

AN XY:

73740

show subpopulations

Gnomad4 AFR

AF:

0.00109

Gnomad4 AMR

AF:

0.00697

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000979

Gnomad4 SAS

AF:

0.00230

Gnomad4 FIN

AF:

0.00800

Gnomad4 NFE

AF:

0.00292

Gnomad4 OTH

AF:

0.00337

Alfa

AF:

0.00123

Hom.:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000588

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CYP21A2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 05, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.5

DANN

Benign

0.76

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0022

M_CAP

Benign

0.041

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.21

N;.;N;.

REVEL

Benign

0.034

Sift

Benign

1.0

T;.;T;.

Sift4G

Benign

1.0

T;.;T;.

Polyphen

0.0010

B;B;.;B

Vest4

0.069

MutPred

0.44

Loss of ubiquitination at K183 (P = 0.0962);Loss of ubiquitination at K183 (P = 0.0962);.;Loss of ubiquitination at K183 (P = 0.0962);

MVP

0.39

MPC

0.43

ClinPred

0.000024

GERP RS

-3.4

gMVP

0.076

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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