rs6451

Positions:

• chr6-32039027-C-A
• chr6-32039027-C-G
• chr6-32039027-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000500.9(CYP21A2):​c.293-67C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,547,130 control chromosomes in the GnomAD database, including 13,939 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1506 hom., cov: 31)
  • Exomes 𝑓: 0.12 (12433 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-32039027-C-A is Benign according to our data. Variant chr6-32039027-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.293-67C>A		intron_variant		ENST00000644719.2
CYP21A2	NM_001128590.4	c.203-67C>A		intron_variant
CYP21A2	NM_001368143.2	c.-132-48C>A		intron_variant
CYP21A2	NM_001368144.2	c.-132-48C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.293-67C>A		intron_variant			NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19833 AN: 151620 Hom.: 1507 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.0734

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.125 AC: 20759 AN: 166540 Hom.: 1938 AF XY: 0.134 AC XY: 11958 AN XY: 89052

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.0624

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.0973

Gnomad SAS exome AF: 0.272

Gnomad FIN exome AF: 0.0772

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.117 AC: 162735 AN: 1395394 Hom.: 12433 Cov.: 40 AF XY: 0.121 AC XY: 83336 AN XY: 689480

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.0693

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.271

Gnomad4 FIN exome AF: 0.0795

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.131 AC: 19846 AN: 151736 Hom.: 1506 Cov.: 31 AF XY: 0.132 AC XY: 9761 AN XY: 74138

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.0733

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.0753

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.121

Alfa AF: 0.0755 Hom.: 114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.46
DANN	Benign	0.64

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: rs6451; hg19: chr6-32006804;