rs6458

chr6-32039847-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000500.9(CYP21A2):c.738+12A>G 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 1,603,274 control chromosomes in the GnomAD database, including 12,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1808 hom., cov: 31)
  • Exomes 𝑓: 0.11 (10413 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.57

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-32039847-A-G is Benign according to our data. Variant chr6-32039847-A-G is described in ClinVar as [Benign]. Clinvar id is 256298.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32039847-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.738+12A>G		intron_variant		ENST00000644719.2
CYP21A2	NM_001128590.4	c.648+12A>G		intron_variant
CYP21A2	NM_001368143.2	c.333+12A>G		intron_variant
CYP21A2	NM_001368144.2	c.333+12A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.738+12A>G		intron_variant			NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22251 AN: 151392 Hom.: 1800 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0700

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.131 AC: 31911 AN: 242802 Hom.: 2351 AF XY: 0.135 AC XY: 17711 AN XY: 131182

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.0973

Gnomad SAS exome AF: 0.238

Gnomad FIN exome AF: 0.0718

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.115 AC: 166679 AN: 1451760 Hom.: 10413 Cov.: 80 AF XY: 0.119 AC XY: 85600 AN XY: 721856

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.0752

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.147 AC: 22282 AN: 151514 Hom.: 1808 Cov.: 31 AF XY: 0.148 AC XY: 10926 AN XY: 74036

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.0700

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.194

Alfa AF: 0.0739 Hom.: 134

Bravo AF: 0.158

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.39
Dann	Benign	0.71

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: rs6458; hg19: chr6-32007624; COSMIC: COSV64483665; COSMIC: COSV64483665;