rs566065375

chr6-32039172-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_000500.9(CYP21A2):c.371C>T(p.Thr124Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,607,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (4 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a helix (size 14) in uniprot entity CP21A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000500.9
• BP4: Computational evidence support a benign effect (MetaRNN=0.012173027).
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.371C>T	p.Thr124Ile	missense_variant	3/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.281C>T	p.Thr94Ile	missense_variant	2/9
CYP21A2	NM_001368143.2	c.-35C>T		5_prime_UTR_variant	3/10
CYP21A2	NM_001368144.2	c.-35C>T		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.371C>T	p.Thr124Ile	missense_variant	3/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152036 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00581

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000619 AC: 147 AN: 237412 Hom.: 3 AF XY: 0.000624 AC XY: 80 AN XY: 128208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00769

Gnomad SAS exome AF: 0.000313

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.000107 AC: 155 AN: 1454892 Hom.: 4 Cov.: 75 AF XY: 0.000122 AC XY: 88 AN XY: 722962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00276

Gnomad4 SAS exome AF: 0.000318

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152154 Hom.: 1 Cov.: 31 AF XY: 0.000309 AC XY: 23 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00544

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000234

ExAC AF: 0.000643 AC: 78

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Feb 16, 2023

Variant summary: CYP21A2 c.371C>T (p.Thr124Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 237412 control chromosomes, predominantly at a frequency of 0.0077 within the East Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in CYP21A2 causing severe Congenital Adrenal Hyperplasia phenotype (0.002), however the prevalence of nonclassic adrenal hyperplasia might be much higher in certain ethnic groups (see e.g. PMIDs 26082286, 29035424), therefore this frequency might not exclude that the variant is associated with disease. The variant, c.371C>T, has been reported in the literature in individuals affected with Congenital Adrenal Hyperplasia (e.g. Wang_2016, Hou_2019, Chi_2019, Hou_2020, Wan_2023), however, in at least two of these cases the variant occurred in cis with another (likely) pathogenic variant (Wang_2016, Hou_2019), or was reported without specifying a second variant (Hou_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.030
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.079	N
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;.;N;N;N;.
REVEL	Benign	0.25
Sift	Benign	0.048	D;.;D;D;D;.
Sift4G	Uncertain	0.0090	D;.;D;D;D;.
Polyphen		0.96	D;D;.;.;.;D
Vest4		0.29
MutPred		0.60		Gain of catalytic residue at L129 (P = 0.0394);Gain of catalytic residue at L129 (P = 0.0394);.;Gain of catalytic residue at L129 (P = 0.0394);.;Gain of catalytic residue at L129 (P = 0.0394);
MVP		0.77
MPC		1.2
ClinPred		0.076	T
GERP RS		3.8
gMVP		0.47

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

Other links and lift over

dbSNP: rs566065375; hg19: chr6-32006949;