rs6467

Positions:

Variant summary

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

The NM_000500.9(CYP21A2):c.293-13C>A variant causes a splice polypyrimidine tract, intron 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 Benign (★★).

Frequency

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

Exomes 𝑓: 0.60 ( 254518 hom. )

Failed GnomAD Quality Control

Consequence

CYP21A2
NM_000500.9 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

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 made for transcript

Verdict is Benign. Variant got -20 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 [Benign]. Clinvar id is 196278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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/exons	MANE	Protein
CYP21A2	NM_000500.9 linkuse as main transcript	c.293-13C>A	splice_polypyrimidine_tract_variant, intron_variant		ENST00000644719.2	NP_000491.4
CYP21A2	NM_001368143.2 linkuse as main transcript	c.-126C>A	5_prime_UTR_variant	3/10		NP_001355072.1
CYP21A2	NM_001368144.2 linkuse as main transcript	c.-126C>A	5_prime_UTR_variant	2/9		NP_001355073.1
CYP21A2	NM_001128590.4 linkuse as main transcript	c.203-13C>A	splice_polypyrimidine_tract_variant, intron_variant			NP_001122062.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.293-13C>A		splice_polypyrimidine_tract_variant, intron_variant			NM_000500.9	ENSP00000496625	P1

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

GnomAD3 exomes

AF:

0.637

AC:

141158

AN:

221616

Hom.:

44741

AF XY:

0.635

AC XY:

75748

AN XY:

119232

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 SAS exome

AF:

0.629

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

Gnomad4 AMR exome

AF:

0.733

Gnomad4 ASJ exome

AF:

0.647

Gnomad4 EAS exome

AF:

0.658

Gnomad4 SAS exome

AF:

0.616

Gnomad4 FIN exome

AF:

0.471

Gnomad4 NFE exome

AF:

0.588

Gnomad4 OTH exome

AF:

0.601

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

Gnomad4 AMR

AF:

0.711

Gnomad4 ASJ

AF:

0.636

Gnomad4 EAS

AF:

0.632

Gnomad4 SAS

AF:

0.597

Gnomad4 FIN

AF:

0.436

Gnomad4 NFE

AF:

0.592

Gnomad4 OTH

AF:

0.646

Alfa

AF:

0.561

Hom.:

9188

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: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 23, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2019	- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 12, 2021

- -

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

MutationTaster

Benign

1.0

P;P

PROVEAN

Benign

0.40

REVEL

Benign

0.034

Sift

Benign

0.31

Sift4G

Pathogenic

0.0

ClinPred

0.0018

GERP RS

-0.59

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