6-32040216-G-C

Position:

• chr6-32040216-G-C

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.939+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00765 in 1,609,538 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (333 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.61

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]

CYP21A2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-32040216-G-C is Benign according to our data. Variant chr6-32040216-G-C is described in ClinVar as [Benign]. Clinvar id is 256303.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32040216-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.939+11G>C		intron_variant		ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.849+11G>C		intron_variant			NP_001122062.3
CYP21A2	NM_001368143.2	c.534+11G>C		intron_variant			NP_001355072.1
CYP21A2	NM_001368144.2	c.534+11G>C		intron_variant			NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.939+11G>C		intron_variant			NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1259 AN: 150870 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00912

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.00608

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.00727

GnomAD3 exomes AF: 0.0144 AC: 3548 AN: 246188 Hom.: 89 AF XY: 0.0131 AC XY: 1756 AN XY: 134194

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0896

Gnomad SAS exome AF: 0.00569

Gnomad FIN exome AF: 0.0226

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00858

GnomAD4 exome AF: 0.00758 AC: 11054 AN: 1458554 Hom.: 333 Cov.: 38 AF XY: 0.00748 AC XY: 5425 AN XY: 725624

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.000881

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.00463

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.00373

Gnomad4 OTH exome AF: 0.00790

GnomAD4 genome AF: 0.00833 AC: 1257 AN: 150984 Hom.: 38 Cov.: 33 AF XY: 0.00949 AC XY: 700 AN XY: 73770

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00904

Gnomad4 ASJ AF: 0.000868

Gnomad4 EAS AF: 0.0915

Gnomad4 SAS AF: 0.00587

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00720

Alfa AF: 0.00525 Hom.: 0

Bravo AF: 0.00731

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 16, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6442; hg19: chr6-32007993;