rs1040311

Positions:

• chr6-32039538-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000500.9(CYP21A2):​c.550-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,541,382 control chromosomes in the GnomAD database, including 1,519 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (160 hom., cov: 31)
  • Exomes 𝑓: 0.014 (1359 hom.)
• Consequence: CYP21A2 NM_000500.9 splice_region, intron
• Scores: Splicing: ADA: 0.00006899
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.602

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=-0.91).
• BP6: Variant 6-32039538-T-C is Benign according to our data. Variant chr6-32039538-T-C is described in ClinVar as [Benign]. Clinvar id is 256295.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32039538-T-C is described in Lovd as [Likely_benign]. Variant chr6-32039538-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0385 (5675/147342) while in subpopulation AFR AF= 0.0361 (1459/40360). AF 95% confidence interval is 0.0346. There are 160 homozygotes in gnomad4. There are 2941 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 160 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.550-8T>C		splice_region_variant, intron_variant		ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.460-8T>C		splice_region_variant, intron_variant			NP_001122062.3
CYP21A2	NM_001368143.2	c.145-8T>C		splice_region_variant, intron_variant			NP_001355072.1
CYP21A2	NM_001368144.2	c.145-8T>C		splice_region_variant, intron_variant			NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.550-8T>C		splice_region_variant, intron_variant			NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5672 AN: 147230 Hom.: 161 Cov.: 31

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.0674

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.00870

Gnomad EAS AF: 0.0338

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0337

GnomAD3 exomes AF: 0.0117 AC: 2426 AN: 206788 Hom.: 217 AF XY: 0.0110 AC XY: 1228 AN XY: 111370

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0301

Gnomad SAS exome AF: 0.00808

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00825

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0144 AC: 20021 AN: 1394040 Hom.: 1359 Cov.: 57 AF XY: 0.0147 AC XY: 10150 AN XY: 691804

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.00646

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.0191

Gnomad4 FIN exome AF: 0.0865

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0385 AC: 5675 AN: 147342 Hom.: 160 Cov.: 31 AF XY: 0.0410 AC XY: 2941 AN XY: 71788

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.00870

Gnomad4 EAS AF: 0.0339

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0320

Gnomad4 OTH AF: 0.0333

Alfa AF: 0.0312 Hom.: 17

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	-0.91
CADD	Benign	2.7
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.040		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: rs1040311; hg19: chr6-32007315; COSMIC: COSV64482182; COSMIC: COSV64482182;