Genetic Variant CYP21A2:p.Leu40Leu (chr6-32038540-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001368143.2(CYP21A2):c.-307C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 150,170 control chromosomes in the GnomAD database, including 51,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 51682 hom., cov: 30)

Exomes 𝑓: 0.79 ( 439449 hom. )

Failed GnomAD Quality Control

Consequence

CYP21A2
NM_001368143.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0860

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 (BayesDel_noAF=-0.58).

BP6

Variant 6-32038540-C-T is Benign according to our data. Variant chr6-32038540-C-T is described in ClinVar as [Benign]. Clinvar id is 256286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32038540-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.118C>T	p.Leu40Leu	synonymous_variant	Exon 1 of 10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.118C>T	p.Leu40Leu	synonymous_variant	Exon 1 of 10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.833

AC:

124960

AN:

150056

Hom.:

51626

Cov.:

show subpopulations

Gnomad AFR

AF:

0.908

Gnomad AMI

AF:

0.916

Gnomad AMR

AF:

0.846

Gnomad ASJ

AF:

0.893

Gnomad EAS

AF:

0.751

Gnomad SAS

AF:

0.823

Gnomad FIN

AF:

0.816

Gnomad MID

AF:

0.890

Gnomad NFE

AF:

0.789

Gnomad OTH

AF:

0.846

GnomAD3 exomes

AF:

0.794

AC:

182802

AN:

230114

Hom.:

70820

AF XY:

0.793

AC XY:

99214

AN XY:

125046

show subpopulations

Gnomad AFR exome

AF:

0.885

Gnomad AMR exome

AF:

0.842

Gnomad ASJ exome

AF:

0.874

Gnomad EAS exome

AF:

0.710

Gnomad SAS exome

AF:

0.814

Gnomad FIN exome

AF:

0.791

Gnomad NFE exome

AF:

0.769

Gnomad OTH exome

AF:

0.790

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.787

AC:

1141026

AN:

1450538

Hom.:

439449

Cov.:

121

AF XY:

0.787

AC XY:

567343

AN XY:

720666

show subpopulations

Gnomad4 AFR exome

AF:

0.904

Gnomad4 AMR exome

AF:

0.846

Gnomad4 ASJ exome

AF:

0.881

Gnomad4 EAS exome

AF:

0.723

Gnomad4 SAS exome

AF:

0.813

Gnomad4 FIN exome

AF:

0.790

Gnomad4 NFE exome

AF:

0.778

Gnomad4 OTH exome

AF:

0.792

GnomAD4 genome

AF:

0.833

AC:

125073

AN:

150170

Hom.:

51682

Cov.:

AF XY:

0.832

AC XY:

61039

AN XY:

73322

show subpopulations

Gnomad4 AFR

AF:

0.909

Gnomad4 AMR

AF:

0.846

Gnomad4 ASJ

AF:

0.893

Gnomad4 EAS

AF:

0.752

Gnomad4 SAS

AF:

0.822

Gnomad4 FIN

AF:

0.816

Gnomad4 NFE

AF:

0.789

Gnomad4 OTH

AF:

0.848

Alfa

AF:

0.774

Hom.:

4117

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

6.3

DANN

Benign

0.84

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