Genetic Variant CYP21A2:c.292+15C>T (chr6-32038826-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000500.9(CYP21A2):c.292+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYP21A2
NM_000500.9 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.179

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP21A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CYP21A2	NM_000500.9 link	c.292+15C>T	intron_variant	Intron 2 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4 link	c.202+202C>T	intron_variant	Intron 1 of 8		NP_001122062.3
CYP21A2	NM_001368143.2 link	c.-133+15C>T	intron_variant	Intron 2 of 9		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.-133+202C>T	intron_variant	Intron 1 of 8		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.292+15C>T		intron_variant	Intron 2 of 9		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151884

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1275784

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

639990

African (AFR)

AF:

0.00

AC:

AN:

31118

American (AMR)

AF:

0.00

AC:

AN:

39836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24312

East Asian (EAS)

AF:

0.00

AC:

AN:

38438

South Asian (SAS)

AF:

0.00

AC:

AN:

80644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5414

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

950520

Other (OTH)

AF:

0.00

AC:

AN:

54168

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

(source)

DANN

Benign

0.54

PhyloP100

-0.18

PromoterAI

0.0014

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.31

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over