chr6-32039027-C-A

Variant names:

• chr6-32039027-C-A
• rs6451
• NM_000500.9:c.293-67C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000500.9(CYP21A2):​c.293-67C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,547,130 control chromosomes in the GnomAD database, including 13,939 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1506 hom., cov: 31)
  • Exomes 𝑓: 0.12 (12433 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.293-67C>A		intron_variant	Intron 2 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.203-67C>A		intron_variant	Intron 1 of 8		NP_001122062.3
CYP21A2	NM_001368143.2	c.-132-48C>A		intron_variant	Intron 2 of 9		NP_001355072.1
CYP21A2	NM_001368144.2	c.-132-48C>A		intron_variant	Intron 1 of 8		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.293-67C>A		intron_variant	Intron 2 of 9		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19833 AN: 151620 Hom.: 1507 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.0734

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.125 AC: 20759 AN: 166540 AF XY: 0.134

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.0624

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.0973

Gnomad FIN exome AF: 0.0772

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.117 AC: 162735 AN: 1395394 Hom.: 12433 Cov.: 40 AF XY: 0.121 AC XY: 83336 AN XY: 689480

African (AFR) AF: 0.187 AC: 5920 AN: 31676

American (AMR) AF: 0.0693 AC: 2561 AN: 36946

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 2976 AN: 25148

East Asian (EAS) AF: 0.118 AC: 4263 AN: 36252

South Asian (SAS) AF: 0.271 AC: 21396 AN: 79088

European-Finnish (FIN) AF: 0.0795 AC: 3882 AN: 48826

Middle Eastern (MID) AF: 0.0969 AC: 513 AN: 5292

European-Non Finnish (NFE) AF: 0.106 AC: 113537 AN: 1074310

Other (OTH) AF: 0.133 AC: 7687 AN: 57856

GnomAD4 genome AF: 0.131 AC: 19846 AN: 151736 Hom.: 1506 Cov.: 31 AF XY: 0.132 AC XY: 9761 AN XY: 74138

African (AFR) AF: 0.183 AC: 7547 AN: 41326

American (AMR) AF: 0.0733 AC: 1118 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 386 AN: 3470

East Asian (EAS) AF: 0.112 AC: 576 AN: 5134

South Asian (SAS) AF: 0.285 AC: 1364 AN: 4786

European-Finnish (FIN) AF: 0.0753 AC: 794 AN: 10544

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7565 AN: 67908

Other (OTH) AF: 0.121 AC: 254 AN: 2106

Alfa AF: 0.0755 Hom.: 114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.46
DANN	Benign	0.64
PhyloP100		-0.11
Mutation Taster		=100/0	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: rs6451; hg19: chr6-32006804;