chr6-32040723-G-A

Position:

chr6-32040723-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP5BP4BS1_Supporting

The NM_000500.9(CYP21A2):c.1174G>A(p.Ala392Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,547,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0056 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 0 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:6

Conservation

PhyloP100: 2.31

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;

PP5

Variant 6-32040723-G-A is Pathogenic according to our data. Variant chr6-32040723-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225335.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=5, Pathogenic=2}. Variant chr6-32040723-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0167332). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00562 (852/151616) while in subpopulation SAS AF= 0.0236 (111/4698). AF 95% confidence interval is 0.0201. There are 0 homozygotes in gnomad4. There are 452 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CYP21A2	NM_000500.9 linkuse as main transcript	c.1174G>A	p.Ala392Thr	missense_variant	9/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4 linkuse as main transcript	c.1084G>A	p.Ala362Thr	missense_variant	8/9		NP_001122062.3
CYP21A2	NM_001368143.2 linkuse as main transcript	c.769G>A	p.Ala257Thr	missense_variant	9/10		NP_001355072.1
CYP21A2	NM_001368144.2 linkuse as main transcript	c.769G>A	p.Ala257Thr	missense_variant	8/9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.1174G>A	p.Ala392Thr	missense_variant	9/10		NM_000500.9	ENSP00000496625	P1

Frequencies

GnomAD3 genomes

AF:

0.00562

AC:

852

AN:

151502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00519

Gnomad ASJ

AF:

0.00636

Gnomad EAS

AF:

0.00759

Gnomad SAS

AF:

0.0236

Gnomad FIN

AF:

0.00463

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00678

Gnomad OTH

AF:

0.00431

GnomAD4 exome

AF:

0.00733

AC:

10227

AN:

1395894

Hom.:

Cov.:

AF XY:

0.00812

AC XY:

5661

AN XY:

697232

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00294

Gnomad4 ASJ exome

AF:

0.00618

Gnomad4 EAS exome

AF:

0.00522

Gnomad4 SAS exome

AF:

0.0281

Gnomad4 FIN exome

AF:

0.00571

Gnomad4 NFE exome

AF:

0.00620

Gnomad4 OTH exome

AF:

0.00796

GnomAD4 genome

AF:

0.00562

AC:

852

AN:

151616

Hom.:

Cov.:

AF XY:

0.00610

AC XY:

452

AN XY:

74074

show subpopulations

Gnomad4 AFR

AF:

0.00193

Gnomad4 AMR

AF:

0.00518

Gnomad4 ASJ

AF:

0.00636

Gnomad4 EAS

AF:

0.00761

Gnomad4 SAS

AF:

0.0236

Gnomad4 FIN

AF:

0.00463

Gnomad4 NFE

AF:

0.00680

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00497

Hom.:

ExAC

AF:

0.0109

AC:

1321

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Pathogenic:5Uncertain:3

Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 20, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.872%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.39; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP21A2 related disorder (ClinVar ID: VCV000225335 / PMID: 17119906). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.A392T in CYP21A2 (NM_000500.9) has been reported in compound heterozygous state in a child with congenital adrenal hyperplasia with 21 hydroxylase deficiency (Robins et al,2007). It has been submitted to ClinVar with varying interpretations: Pathogenic/Likely Pathogenic/ Uncertain Significance. Although the variant is present at 0.9213% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.A392T variant is novel (not in any individuals) in 1000 Genomes. The p.A392T missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1174 in CYP21A2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.In the absence of another reportable variant, the molecular diagnosis of 21 hydroxylase deficiency is not confirmed. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital adrenal hyperplasia, due to 21-hydroxylase deficiency. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (2320 heterozygotes, 0 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (7 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytochrome P450 domain (NCBI, PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The alternative change to a valine has been found in trans in an individual with congenital adrenal hyperplasia (PMID: 19531083). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. The variants has previously been reported as pathogenic (ClinVar, LOVD, VCGS, PMID: 17119906, 32616876) in patients with congenital adrenal hyperplasia, however it has also been classified as a VUS (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected COS-1 cells showed a significant reduction in enzyme activity and maximum velocity (PMID: 17119906). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Mar 10, 2021	Found in heterozygous state in a male 8 year old boy with precaucious puberty child. No other variant detected -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

not provided

Pathogenic:4Uncertain:2

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CYP21A2 p.Ala362Thr variant was identified as a compound heterozygous variant with a CYP21A2 p.V282L variant in a girl with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase; compound heterozygousity was confirmed through genotyping of the parents (Robins_2007_PMID:17119906). Whole exome sequencing of 43 children with a diagnosis of familial glucocorticoid deficiency identified the p.A362T variant as a heterozygous variant in one patient; a second variant was not identified (Chan_2015_PMID:26300845). The variant was identified in dbSNP (ID: rs202242769), ClinVar (classified as pathogenic by Fulgent Genetics and as likely pathogenic by Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 2320 of 266040 chromosomes (0 homozygous) at a frequency of 0.00872 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 846 of 29396 chromosomes (freq: 0.02878), East Asian in 153 of 19106 chromosomes (freq: 0.008008), European (non-Finnish) in 929 of 119756 chromosomes (freq: 0.007757), Ashkenazi Jewish in 75 of 10030 chromosomes (freq: 0.007478), Other in 41 of 6796 chromosomes (freq: 0.006033), European (Finnish) in 125 of 23452 chromosomes (freq: 0.00533), Latino in 114 of 34736 chromosomes (freq: 0.003282), and African in 37 of 22768 chromosomes (freq: 0.001625). The p.Ala362 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 02, 2021	This sequence change replaces alanine with threonine at codon 392 of the CYP21A2 protein (p.Ala392Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This missense change has been observed in individual(s) with simple virilizing and nonclassical congenital adrenal hyperplasia (PMID: 17119906, 21750395). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as A391T and c.2296G>A (p.Ala391Thr). ClinVar contains an entry for this variant (Variation ID: 225335). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP21A2 protein function. Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 17119906). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 21, 2023	Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity. This variant is also referred to as p.Ala391Thr in published literature. This variant has been identified in at least one individual with non-classic congenital adrenal hyperplasia (CAH). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17119906) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 14, 2023

Variant summary: CYP21A2 c.1174G>A (p.Ala392Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0092 in 234892 control chromosomes (gnomAD). Due to high homology with the CYP21A1P pseudogene, allele frequency data from the general population is uninformative for the assessment of this variant. c.1174G>A has been reported in the literature in at least one compound heterozygous individual affected with Congenital Adrenal Hyperplasia (e.g. Robins_2007). These data do not allow any conclusion about variant significance. Transient expression in COS-1 cells have demonstrated the variant has 38.9% enzymatic activity for the conversion of 17-OHP and 22.9% activity for progesterone (Robins_2007). Eight ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, three as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

MetaRNN

Benign

0.017

T;T;T;T

MetaSVM

Benign

-0.45

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

N;.;N;.

REVEL

Uncertain

0.39

Sift

Benign

0.22

T;.;T;.

Sift4G

Uncertain

0.0090

D;.;D;.

Polyphen

1.0

D;D;.;D

Vest4

0.21

MPC

2.9

ClinPred

0.96

GERP RS

3.9

gMVP

0.82

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