rs767333157

chr6-32040952-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000500.9(CYP21A2):c.1306C>T(p.Arg436Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.448

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 -2 ACMG points.

• PM1: In a helix (size 15) 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=0.015557289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.1306C>T	p.Arg436Cys	missense_variant	10/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.1216C>T	p.Arg406Cys	missense_variant	9/9
CYP21A2	NM_001368143.2	c.901C>T	p.Arg301Cys	missense_variant	10/10
CYP21A2	NM_001368144.2	c.901C>T	p.Arg301Cys	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.1306C>T	p.Arg436Cys	missense_variant	10/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.000889 AC: 134 AN: 150780 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.00214 AC: 287 AN: 134056 Hom.: 0 AF XY: 0.00187 AC XY: 136 AN XY: 72886

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.0000817

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0259

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000489

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000839 AC: 868 AN: 1034512 Hom.: 0 Cov.: 15 AF XY: 0.000789 AC XY: 414 AN XY: 524402

Gnomad4 AFR exome AF: 0.000110

Gnomad4 AMR exome AF: 0.0000567

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0193

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.0000259

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.00165

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000888 AC: 134 AN: 150896 Hom.: 0 Cov.: 33 AF XY: 0.000733 AC XY: 54 AN XY: 73630

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000104

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.000528 Hom.: 0

ExAC AF: 0.000313 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 16, 2022	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CYP21A2: PP2, PP3, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.28	N
MetaRNN	Benign	0.016	T;T;T;T
MetaSVM	Uncertain	0.21	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.5	D;.;D;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		1.0	D;D;.;D
Vest4		0.77
MutPred		0.92		Loss of methylation at R436 (P = 0.0139);Loss of methylation at R436 (P = 0.0139);.;Loss of methylation at R436 (P = 0.0139);
MVP		0.93
MPC		3.5
ClinPred		0.16	T
GERP RS		4.5
gMVP		0.68

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: rs767333157; hg19: chr6-32008729; COSMIC: COSV64478243; COSMIC: COSV64478243;