6-32039119-G-C

Position:

• chr6-32039119-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_000500.9(CYP21A2):​c.318G>C​(p.Pro106Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,483,998 control chromosomes in the GnomAD database, including 1,046 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. P106P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.025 (141 hom., cov: 31)
  • Exomes 𝑓: 0.025 (905 hom.)
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-32039119-G-C is Benign according to our data. Variant chr6-32039119-G-C is described in ClinVar as [Benign]. Clinvar id is 256293.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32039119-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0254 (3630/143174) while in subpopulation NFE AF= 0.0254 (1664/65546). AF 95% confidence interval is 0.0244. There are 141 homozygotes in gnomad4. There are 2105 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 141 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.318G>C	p.Pro106Pro	synonymous_variant	3/10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.228G>C	p.Pro76Pro	synonymous_variant	2/9		NP_001122062.3
CYP21A2	NM_001368143.2	c.-88G>C		5_prime_UTR_variant	3/10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-88G>C		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>C	p.Pro106Pro	synonymous_variant	3/10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3629 AN: 143064 Hom.: 141 Cov.: 31

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0850

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000689

Gnomad SAS AF: 0.00957

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.0229 AC: 5585 AN: 244218 Hom.: 211 AF XY: 0.0223 AC XY: 2936 AN XY: 131930

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00458

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0247 AC: 33124 AN: 1340824 Hom.: 905 Cov.: 75 AF XY: 0.0241 AC XY: 16010 AN XY: 665058

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.000368

Gnomad4 EAS exome AF: 0.000437

Gnomad4 SAS exome AF: 0.00628

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0254 AC: 3630 AN: 143174 Hom.: 141 Cov.: 31 AF XY: 0.0304 AC XY: 2105 AN XY: 69312

Gnomad4 AFR AF: 0.00431

Gnomad4 AMR AF: 0.00864

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000690

Gnomad4 SAS AF: 0.00979

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00660 Hom.: 3

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	-0.92
CADD	Benign	0.63
DANN	Benign	0.58

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: rs6455; hg19: chr6-32006896; COSMIC: COSV64473697; COSMIC: COSV64473697;