rs184649564

chr6-32041085-G-Achr6-32041085-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000500.9(CYP21A2):c.1439G>A(p.Arg480Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,572,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R480L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.139

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a strand (size 4) in uniprot entity CP21A_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000500.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-32041084-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2201488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.1439G>A	p.Arg480Gln	missense_variant	10/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.1349G>A	p.Arg450Gln	missense_variant	9/9
CYP21A2	NM_001368143.2	c.1034G>A	p.Arg345Gln	missense_variant	10/10
CYP21A2	NM_001368144.2	c.1034G>A	p.Arg345Gln	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.1439G>A	p.Arg480Gln	missense_variant	10/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151614 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000188 AC: 4 AN: 213178 Hom.: 0 AF XY: 0.0000257 AC XY: 3 AN XY: 116676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000699

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000134 AC: 19 AN: 1420684 Hom.: 0 Cov.: 32 AF XY: 0.0000113 AC XY: 8 AN XY: 706112

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000137

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151732 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74158

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000168 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	16
Dann	Benign	0.92
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.080	N
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.93	N;.;N;.
REVEL	Benign	0.15
Sift	Benign	0.42	T;.;T;.
Sift4G	Benign	0.15	T;.;T;.
Polyphen		0.060	B;B;.;B
Vest4		0.092
MutPred		0.58		Loss of MoRF binding (P = 0.0263);Loss of MoRF binding (P = 0.0263);.;Loss of MoRF binding (P = 0.0263);
MVP		0.49
MPC		0.011
ClinPred		0.055	T
GERP RS		0.38
gMVP		0.52

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: rs184649564; hg19: chr6-32008862;