rs6469

chr6-32040674-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000500.9(CYP21A2):c.1125C>T(p.Ser375=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 146,200 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S375S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (439 hom., cov: 33)
  • Exomes 𝑓: 0.16 (3961 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.43

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-32040674-C-T is Benign according to our data. Variant chr6-32040674-C-T is described in ClinVar as [Benign]. Clinvar id is 256285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32040674-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.1125C>T	p.Ser375=	synonymous_variant	9/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.1035C>T	p.Ser345=	synonymous_variant	8/9
CYP21A2	NM_001368143.2	c.720C>T	p.Ser240=	synonymous_variant	9/10
CYP21A2	NM_001368144.2	c.720C>T	p.Ser240=	synonymous_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.1125C>T	p.Ser375=	synonymous_variant	9/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 24206 AN: 146080 Hom.: 441 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.171

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.164 AC: 228468 AN: 1390034 Hom.: 3961 Cov.: 34 AF XY: 0.164 AC XY: 113449 AN XY: 691930

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.271

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.166 AC: 24235 AN: 146200 Hom.: 439 Cov.: 33 AF XY: 0.166 AC XY: 11866 AN XY: 71394

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.171

Alfa AF: 0.189 Hom.: 73

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	4.9
Dann	Benign	0.89

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: rs6469; hg19: chr6-32008451; COSMIC: COSV64473267; COSMIC: COSV64473267;