rs6464

chr6-32038560-C-Achr6-32038560-C-Gchr6-32038560-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.138C>A(p.Pro46=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 150,242 control chromosomes in the GnomAD database, including 36,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (36743 hom., cov: 29)
  • Exomes 𝑓: 0.70 (340401 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.442

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=-0.68).
• BP6: Variant 6-32038560-C-A is Benign according to our data. Variant chr6-32038560-C-A is described in ClinVar as [Benign]. Clinvar id is 256287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32038560-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.442 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.138C>A	p.Pro46=	synonymous_variant	1/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.138C>A	p.Pro46=	synonymous_variant	1/9
CYP21A2	NM_001368143.2	c.-287C>A		5_prime_UTR_variant	1/10
CYP21A2	NM_001368144.2	c.-197C>A		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.138C>A	p.Pro46=	synonymous_variant	1/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.709 AC: 106472 AN: 150122 Hom.: 36709 Cov.: 29

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.904

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.697

GnomAD3 exomes AF: 0.689 AC: 146582 AN: 212814 Hom.: 48011 AF XY: 0.685 AC XY: 79271 AN XY: 115772

Gnomad AFR exome AF: 0.659

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.745

Gnomad EAS exome AF: 0.636

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.727

Gnomad NFE exome AF: 0.678

Gnomad OTH exome AF: 0.674

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.700 AC: 1010880 AN: 1444304 Hom.: 340401 Cov.: 96 AF XY: 0.698 AC XY: 500628 AN XY: 717004

Gnomad4 AFR exome AF: 0.679

Gnomad4 AMR exome AF: 0.770

Gnomad4 ASJ exome AF: 0.740

Gnomad4 EAS exome AF: 0.615

Gnomad4 SAS exome AF: 0.642

Gnomad4 FIN exome AF: 0.730

Gnomad4 NFE exome AF: 0.703

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.709 AC: 106560 AN: 150242 Hom.: 36743 Cov.: 29 AF XY: 0.708 AC XY: 51976 AN XY: 73366

Gnomad4 AFR AF: 0.691

Gnomad4 AMR AF: 0.733

Gnomad4 ASJ AF: 0.742

Gnomad4 EAS AF: 0.691

Gnomad4 SAS AF: 0.664

Gnomad4 FIN AF: 0.761

Gnomad4 NFE AF: 0.708

Gnomad4 OTH AF: 0.700

Alfa AF: 0.545 Hom.: 3400

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

-

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	5.0
Dann	Benign	0.83

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: rs6464; hg19: chr6-32006337; COSMIC: COSV64481742; COSMIC: COSV64481742;