6-32039027-C-G

Variant names:

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

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>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.05 in 1,555,474 control chromosomes in the GnomAD database, including 2,302 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 0.075 (578 hom., cov: 31)
  • Exomes 𝑓: 0.047 (1724 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.293-67C>G		intron_variant	Intron 2 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.203-67C>G		intron_variant	Intron 1 of 8		NP_001122062.3
CYP21A2	NM_001368143.2	c.-132-48C>G		intron_variant	Intron 2 of 9		NP_001355072.1
CYP21A2	NM_001368144.2	c.-132-48C>G		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>G		intron_variant	Intron 2 of 9		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0752 AC: 11407 AN: 151626 Hom.: 578 Cov.: 31

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0917

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.0693

Gnomad FIN AF: 0.0100

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0438

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0568 AC: 9467 AN: 166540 AF XY: 0.0577

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0584

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.0202

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0486

Gnomad OTH exome AF: 0.0735

GnomAD4 exome AF: 0.0472 AC: 66304 AN: 1403730 Hom.: 1724 Cov.: 40 AF XY: 0.0481 AC XY: 33387 AN XY: 693492

African (AFR) AF: 0.157 AC: 4994 AN: 31848

American (AMR) AF: 0.0630 AC: 2328 AN: 36974

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 1902 AN: 25232

East Asian (EAS) AF: 0.0122 AC: 445 AN: 36346

South Asian (SAS) AF: 0.0828 AC: 6613 AN: 79882

European-Finnish (FIN) AF: 0.0114 AC: 559 AN: 48838

Middle Eastern (MID) AF: 0.154 AC: 816 AN: 5308

European-Non Finnish (NFE) AF: 0.0419 AC: 45331 AN: 1081126

Other (OTH) AF: 0.0570 AC: 3316 AN: 58176

GnomAD4 genome AF: 0.0751 AC: 11403 AN: 151744 Hom.: 578 Cov.: 31 AF XY: 0.0748 AC XY: 5547 AN XY: 74142

African (AFR) AF: 0.144 AC: 5943 AN: 41306

American (AMR) AF: 0.0916 AC: 1398 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 277 AN: 3470

East Asian (EAS) AF: 0.0230 AC: 118 AN: 5134

South Asian (SAS) AF: 0.0695 AC: 334 AN: 4804

European-Finnish (FIN) AF: 0.0100 AC: 106 AN: 10554

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0438 AC: 2974 AN: 67912

Other (OTH) AF: 0.0993 AC: 209 AN: 2104

Alfa AF: 0.0322 Hom.: 114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.55
DANN	Benign	0.58
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV107499750; COSMIC: COSV107499750;