chr6-32039081-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001368143.2(CYP21A2):c.-126C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 151,196 control chromosomes in the GnomAD database, including 28,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.61 ( 28032 hom., cov: 29)

Exomes 𝑓: 0.60 ( 254518 hom. )

Failed GnomAD Quality Control

Consequence

CYP21A2
NM_001368143.2 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:9

Conservation

PhyloP100: -0.233

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7294652E-6).

BP6

Variant 6-32039081-C-A is Benign according to our data. Variant chr6-32039081-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196278.We mark this variant Likely_benign, oryginal submissions are: {Pathogenic=1, Benign=7}. Variant chr6-32039081-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.293-13C>A	intron_variant	Intron 2 of 9	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
CYP21A2	NM_001368143.2 link	c.-126C>A	5_prime_UTR_variant	Exon 3 of 10		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.-126C>A	5_prime_UTR_variant	Exon 2 of 9		NP_001355073.1
CYP21A2	NM_001128590.4 link	c.203-13C>A	intron_variant	Intron 1 of 8		NP_001122062.3	P08686Q08AG9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.293-13C>A		intron_variant	Intron 2 of 9		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

91969

AN:

151080

Hom.:

28000

Cov.:

show subpopulations

Gnomad AFR

AF:

0.637

Gnomad AMI

AF:

0.639

Gnomad AMR

AF:

0.711

Gnomad ASJ

AF:

0.636

Gnomad EAS

AF:

0.631

Gnomad SAS

AF:

0.596

Gnomad FIN

AF:

0.436

Gnomad MID

AF:

0.621

Gnomad NFE

AF:

0.592

Gnomad OTH

AF:

0.644

GnomAD2 exomes

AF:

0.637

AC:

141158

AN:

221616

AF XY:

0.635

show subpopulations

Gnomad AFR exome

AF:

0.675

Gnomad AMR exome

AF:

0.739

Gnomad ASJ exome

AF:

0.659

Gnomad EAS exome

AF:

0.634

Gnomad FIN exome

AF:

0.475

Gnomad NFE exome

AF:

0.630

Gnomad OTH exome

AF:

0.644

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.595

AC:

857154

AN:

1440498

Hom.:

254518

Cov.:

AF XY:

0.596

AC XY:

425953

AN XY:

714448

show subpopulations

Gnomad4 AFR exome

AF:

0.644

AC:

21316

AN:

33106

Gnomad4 AMR exome

AF:

0.733

AC:

31315

AN:

42702

Gnomad4 ASJ exome

AF:

0.647

AC:

16619

AN:

25696

Gnomad4 EAS exome

AF:

0.658

AC:

25592

AN:

38918

Gnomad4 SAS exome

AF:

0.616

AC:

51270

AN:

83168

Gnomad4 FIN exome

AF:

0.471

AC:

24176

AN:

51358

Gnomad4 NFE exome

AF:

0.588

AC:

647335

AN:

1100550

Gnomad4 Remaining exome

AF:

0.601

AC:

35814

AN:

59562

Heterozygous variant carriers

16994

33987

50981

67974

84968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

17870

35740

53610

71480

89350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.609

AC:

92050

AN:

151196

Hom.:

28032

Cov.:

AF XY:

0.605

AC XY:

44652

AN XY:

73832

show subpopulations

Gnomad4 AFR

AF:

0.636

AC:

0.636383

AN:

0.636383

Gnomad4 AMR

AF:

0.711

AC:

0.711339

AN:

0.711339

Gnomad4 ASJ

AF:

0.636

AC:

0.635892

AN:

0.635892

Gnomad4 EAS

AF:

0.632

AC:

0.631631

AN:

0.631631

Gnomad4 SAS

AF:

0.597

AC:

0.597321

AN:

0.597321

Gnomad4 FIN

AF:

0.436

AC:

0.436317

AN:

0.436317

Gnomad4 NFE

AF:

0.592

AC:

0.591779

AN:

0.591779

Gnomad4 OTH

AF:

0.646

AC:

0.645992

AN:

0.645992

Heterozygous variant carriers

1468

2936

4403

5871

7339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.569

Hom.:

10792

Bravo

AF:

0.636

TwinsUK

AF:

0.614

AC:

2275

ALSPAC

AF:

0.607

AC:

2338

ESP6500AA

AF:

0.656

AC:

2883

ESP6500EA

AF:

0.616

AC:

5296

ExAC

AF:

0.608

AC:

73208

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Pathogenic:1Benign:3

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The intron variant c.293-13C>A variant in CYP21A2 gene, also known as In2G variant, represents the most common CYP21A2 gene changes related to the classic 21OHD form. The In2G variant is frequent in patients with 21OHD (Kocova et al., 2022). The c.293-13C>A variant is present with allele frequency of 0.63% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Benign. It normally causes severe disease; however, the clinical presentation can vary from the SW form, through the SV form and rarely the NC form. Thus, there is a difference in the severity of 21OHD within group A. The mechanism underlying the variation in the clinical phenotype of the In2G variant was widely discussed. The most accredited hypothesis is that a small number of transcripts avoid aberrant splicing, providing a small amount of the 21- hydroxylase enzyme, which is sufficient for a milder clinical presentation of the disease (Kocova et al., 2022). For these reasons, this variant has been classified as Pathogenic. -

May 12, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 2019

GeneDx

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

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.0

DANN

Benign

0.44

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0000017

MetaSVM

Benign

-1.0

PROVEAN

Benign

0.40

REVEL

Benign

0.034

Sift

Benign

0.31

Sift4G

Pathogenic

0.0

ClinPred

0.0018

GERP RS

-0.59

Mutation Taster

=47/41

disease causing (ClinVar)

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