6-32038471-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000500.9(CYP21A2):c.49C>T(p.Arg17Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,575,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R17L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.226

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34996212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP21A2	NM_000500.9 linkuse as main transcript	c.49C>T	p.Arg17Cys	missense_variant	1/10	ENST00000644719.2
CYP21A2	NM_001128590.4 linkuse as main transcript	c.49C>T	p.Arg17Cys	missense_variant	1/9
CYP21A2	NM_001368143.2 linkuse as main transcript	c.-376C>T		5_prime_UTR_variant	1/10
CYP21A2	NM_001368144.2 linkuse as main transcript	c.-286C>T		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.49C>T	p.Arg17Cys	missense_variant	1/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000107

AC:

AN:

186390

Hom.:

AF XY:

0.0000196

AC XY:

AN XY:

101786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000262

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000204

AC:

AN:

1423264

Hom.:

Cov.:

103

AF XY:

0.0000213

AC XY:

AN XY:

704810

show subpopulations

Gnomad4 AFR exome

AF:

0.0000309

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000238

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 25, 2023

Variant summary: CYP21A2 c.49C>T (p.Arg17Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 186390 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.49C>T has been reported in the literature as a heterozygous genotype in at-least one individual with a suspicion of Congenital Adrenal Hyperplasia (example, de Paula_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. At least one publication reports experimental evidence evaluating an impact on protein function (de Paula_2016). The most pronounced variant effect results in >80%-90% of normal CYP21A2 activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 32616876, 27721825). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense c.49C>T p.Arg17Cys variant in the CYP21A2 gene has been reported in heterozygous carriers and it demonstrated a very mild reduction in enzyme activity, de Paula Michelatto, Débora et al.,2016. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Uncertain Significance. The amino acid Arginine at position 17 is changed to a Cystine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg17Cys in CYP21A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.0096

BayesDel_noAF

Benign

-0.16

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.024

M_CAP

Benign

0.074

MetaRNN

Benign

0.35

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.4

N;.;D;D;N;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.0070

D;.;D;D;D;.

Sift4G

Uncertain

0.0040

D;.;D;D;D;.

Polyphen

0.99

D;D;.;.;.;D

Vest4

0.17

MVP

0.71

MPC

2.4

ClinPred

0.75

GERP RS

2.6

gMVP

0.41

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