rs1040312

chr6-32039531-C-A

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.550-15C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,550,408 control chromosomes in the GnomAD database, including 1,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (196 hom., cov: 31)
  • Exomes 𝑓: 0.014 (1045 hom.)
• Consequence: CYP21A2 NM_000500.9 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.477

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=-0.86).
• BP6: Variant 6-32039531-C-A is Benign according to our data. Variant chr6-32039531-C-A is described in ClinVar as [Benign]. Clinvar id is 256294.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32039531-C-A is described in Lovd as [Likely_benign]. Variant chr6-32039531-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.550-15C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000644719.2
CYP21A2	NM_001128590.4	c.460-15C>A		splice_polypyrimidine_tract_variant, intron_variant
CYP21A2	NM_001368143.2	c.145-15C>A		splice_polypyrimidine_tract_variant, intron_variant
CYP21A2	NM_001368144.2	c.145-15C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.550-15C>A		splice_polypyrimidine_tract_variant, intron_variant			NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6330 AN: 147382 Hom.: 197 Cov.: 31

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.0661

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.00783

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.0223

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0449

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0380

GnomAD3 exomes AF: 0.0129 AC: 2652 AN: 205752 Hom.: 191 AF XY: 0.0118 AC XY: 1303 AN XY: 110670

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0335

Gnomad SAS exome AF: 0.00788

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00761

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0136 AC: 19089 AN: 1402910 Hom.: 1045 Cov.: 61 AF XY: 0.0138 AC XY: 9599 AN XY: 695690

Gnomad4 AFR exome AF: 0.0409

Gnomad4 AMR exome AF: 0.0201

Gnomad4 ASJ exome AF: 0.00626

Gnomad4 EAS exome AF: 0.0176

Gnomad4 SAS exome AF: 0.0185

Gnomad4 FIN exome AF: 0.0776

Gnomad4 NFE exome AF: 0.00906

Gnomad4 OTH exome AF: 0.0176

GnomAD4 genome AF: 0.0430 AC: 6340 AN: 147498 Hom.: 196 Cov.: 31 AF XY: 0.0449 AC XY: 3224 AN XY: 71834

Gnomad4 AFR AF: 0.0584

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.00783

Gnomad4 EAS AF: 0.0371

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.0294

Gnomad4 OTH AF: 0.0376

Alfa AF: 0.0319 Hom.: 23

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	-0.86
Cadd	Benign	2.2
Dann	Benign	0.75

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: rs1040312; hg19: chr6-32007308; COSMIC: COSV64482179; COSMIC: COSV64482179;