6-32041097-G-C

Position:

• chr6-32041097-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_000500.9(CYP21A2):​c.1451G>C​(p.Arg484Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,582,546 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R484?) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 1.19

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-32041097-GG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 6-32041097-G-C is Pathogenic according to our data. Variant chr6-32041097-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1264335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32041097-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.1451G>C	p.Arg484Pro	missense_variant	10/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.1361G>C	p.Arg454Pro	missense_variant	9/9
CYP21A2	NM_001368143.2	c.1046G>C	p.Arg349Pro	missense_variant	10/10
CYP21A2	NM_001368144.2	c.1046G>C	p.Arg349Pro	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.1451G>C	p.Arg484Pro	missense_variant	10/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.000352 AC: 53 AN: 150672 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.000712

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000330 AC: 75 AN: 227246 Hom.: 0 AF XY: 0.000305 AC XY: 38 AN XY: 124498

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000717 AC: 1027 AN: 1431756 Hom.: 0 Cov.: 33 AF XY: 0.000679 AC XY: 484 AN XY: 712384

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000685

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000470

Gnomad4 FIN exome AF: 0.0000457

Gnomad4 NFE exome AF: 0.000901

Gnomad4 OTH exome AF: 0.000337

GnomAD4 genome AF: 0.000351 AC: 53 AN: 150790 Hom.: 0 Cov.: 33 AF XY: 0.000231 AC XY: 17 AN XY: 73644

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000712

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000373 Hom.: 0

ExAC AF: 0.000283 AC: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:2 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Mar 10, 2021	- -
Likely pathogenic, 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: 0.033%). However, 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. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.66; 3Cnet: 0.29). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001264335). A different missense change at the same codon (p.Arg484Gln, p.Arg484Trp) has been reported to be associated with CYP21A2 related disorder (ClinVar ID: VCV000585750 / PMID: 12915679, 14715874). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 25, 2015	The CYP21A2 c.1451G>C (p.Arg484Pro) pathogenic variant (also known as R483P) has been described to cause markedly decreased CYP21A2 activity and stability, and identified in individuals with CAH, mainly of the salt-wasting phenotype (PMID: 9497336 (1998), 15994751 (2005), 20926536 (2011), and 23359698 (2013), 32616876 (2020)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Benign	-0.037
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.4	D;.;D;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		1.0	D;D;.;D
Vest4		0.73
MVP		0.94
MPC		0.061
ClinPred		0.28	T
GERP RS		4.2
gMVP		0.97

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: rs200005406; hg19: chr6-32008874;