NM_000500.9:c.69G>T

Variant names:

• chr6-32038491-G-T
• rs72552744
• NM_000500.9:c.69G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1 PP2 BP4_Strong

The NM_000500.9(CYP21A2):​c.69G>T​(p.Trp23Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,591,562 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.91
• Publications: 5 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000500.9
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04066196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.69G>T	p.Trp23Cys	missense_variant	Exon 1 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.69G>T	p.Trp23Cys	missense_variant	Exon 1 of 9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-356G>T		5_prime_UTR_variant	Exon 1 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-266G>T		5_prime_UTR_variant	Exon 1 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.69G>T	p.Trp23Cys	missense_variant	Exon 1 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152094 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.000765

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000546 AC: 115 AN: 210526 AF XY: 0.000584

Gnomad AFR exome AF: 0.000167

Gnomad AMR exome AF: 0.000744

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.000559

GnomAD4 exome AF: 0.000514 AC: 740 AN: 1439350 Hom.: 1 Cov.: 104 AF XY: 0.000522 AC XY: 373 AN XY: 714210

African (AFR) AF: 0.0000609 AC: 2 AN: 32858

American (AMR) AF: 0.000601 AC: 25 AN: 41628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 38776

South Asian (SAS) AF: 0.00 AC: 0 AN: 83742

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.000623 AC: 686 AN: 1100548

Other (OTH) AF: 0.000437 AC: 26 AN: 59548

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152212 Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74412

African (AFR) AF: 0.000168 AC: 7 AN: 41552

American (AMR) AF: 0.000654 AC: 10 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000457

ExAC AF: 0.000356 AC: 43

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Aug 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.10	.;.;.;T;.;.
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	.;.;D;D;.;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.041	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
PhyloP100		1.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;.;D;D;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;.;D;D;D;.
Sift4G	Benign	0.087	T;.;D;D;T;.
Polyphen		1.0	D;D;.;.;.;D
Vest4		0.45
MutPred		0.61		Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);Gain of catalytic residue at W23 (P = 0.026);
MVP		0.81
MPC		4.9
ClinPred		0.082	T
GERP RS		3.6
PromoterAI		0.017	Neutral
gMVP		0.62
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs72552744; hg19: chr6-32006268;