rs6455

Positions:

• chr6-32039119-G-A
• chr6-32039119-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000500.9(CYP21A2):​c.318G>A​(p.Pro106Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,484,242 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P106P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0085 (21 hom., cov: 31)
  • Exomes 𝑓: 0.00086 (11 hom.)
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.25

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-32039119-G-A is Benign according to our data. Variant chr6-32039119-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039119-G-A is described in Lovd as [Benign]. Variant chr6-32039119-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00852 (1220/143214) while in subpopulation AFR AF= 0.029 (1137/39224). AF 95% confidence interval is 0.0276. There are 21 homozygotes in gnomad4. There are 595 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.318G>A	p.Pro106Pro	synonymous_variant	3/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.228G>A	p.Pro76Pro	synonymous_variant	2/9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-88G>A		5_prime_UTR_variant	3/10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-88G>A		5_prime_UTR_variant	2/9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.318G>A	p.Pro106Pro	synonymous_variant	3/10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.00851 AC: 1218 AN: 143104 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00453

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000239

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000763

Gnomad OTH AF: 0.00655

GnomAD3 exomes AF: 0.00190 AC: 464 AN: 244218 Hom.: 4 AF XY: 0.00139 AC XY: 183 AN XY: 131930

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.000674

GnomAD4 exome AF: 0.000858 AC: 1150 AN: 1341028 Hom.: 11 Cov.: 75 AF XY: 0.000767 AC XY: 510 AN XY: 665182

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.00173

Gnomad4 ASJ exome AF: 0.0000460

Gnomad4 EAS exome AF: 0.0000336

Gnomad4 SAS exome AF: 0.000166

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.00852 AC: 1220 AN: 143214 Hom.: 21 Cov.: 31 AF XY: 0.00858 AC XY: 595 AN XY: 69336

Gnomad4 AFR AF: 0.0290

Gnomad4 AMR AF: 0.00453

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000763

Gnomad4 OTH AF: 0.00649

Alfa AF: 0.000256 Hom.: 3

Bravo AF: 0.00916

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6455; hg19: chr6-32006896;