6-32039119-G-C

Variant names:

• chr6-32039119-G-C
• rs6455
• NM_000500.9:c.318G>C

Variant summary

Our verdict is Benign. The variant received -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 Likely 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
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256293.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 141 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.318G>C	p.Pro106Pro	synonymous_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.0229 AC: 5585 AN: 244218 AF XY: 0.0223

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 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

African (AFR) AF: 0.00311 AC: 94 AN: 30178

American (AMR) AF: 0.00519 AC: 216 AN: 41590

Ashkenazi Jewish (ASJ) AF: 0.000368 AC: 8 AN: 21740

East Asian (EAS) AF: 0.000437 AC: 13 AN: 29728

South Asian (SAS) AF: 0.00628 AC: 529 AN: 84290

European-Finnish (FIN) AF: 0.155 AC: 6754 AN: 43504

Middle Eastern (MID) AF: 0.00367 AC: 19 AN: 5184

European-Non Finnish (NFE) AF: 0.0238 AC: 24538 AN: 1032370

Other (OTH) AF: 0.0182 AC: 953 AN: 52240

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

African (AFR) AF: 0.00431 AC: 169 AN: 39234

American (AMR) AF: 0.00864 AC: 124 AN: 14358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.000690 AC: 3 AN: 4346

South Asian (SAS) AF: 0.00979 AC: 41 AN: 4188

European-Finnish (FIN) AF: 0.171 AC: 1534 AN: 8946

Middle Eastern (MID) AF: 0.00365 AC: 1 AN: 274

European-Non Finnish (NFE) AF: 0.0254 AC: 1664 AN: 65546

Other (OTH) AF: 0.00899 AC: 18 AN: 2002

Alfa AF: 0.00648 Hom.: 3

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.63
DANN	Benign	0.58
PhyloP100		-2.3
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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