NM_000500.9:c.552C>T

Variant names:

• chr6-32039548-C-T
• rs397515531
• NM_000500.9:c.552C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000500.9(CYP21A2):​c.552C>T​(p.Asp184Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,584,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 splice_region, synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.725
• Publications: 9 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-0.725 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.552C>T	p.Asp184Asp	splice_region_variant, synonymous_variant	Exon 5 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.462C>T	p.Asp154Asp	splice_region_variant, synonymous_variant	Exon 4 of 9		NP_001122062.3
CYP21A2	NM_001368143.2	c.147C>T	p.Asp49Asp	splice_region_variant, synonymous_variant	Exon 5 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.147C>T	p.Asp49Asp	splice_region_variant, synonymous_variant	Exon 4 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.552C>T	p.Asp184Asp	splice_region_variant, synonymous_variant	Exon 5 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000142 AC: 3 AN: 211870 AF XY: 0.00000878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000154 AC: 22 AN: 1432982 Hom.: 0 Cov.: 58 AF XY: 0.0000141 AC XY: 10 AN XY: 710300

African (AFR) AF: 0.00 AC: 0 AN: 32914

American (AMR) AF: 0.0000250 AC: 1 AN: 40034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25714

East Asian (EAS) AF: 0.0000517 AC: 2 AN: 38666

South Asian (SAS) AF: 0.0000360 AC: 3 AN: 83252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000137 AC: 15 AN: 1096208

Other (OTH) AF: 0.0000169 AC: 1 AN: 59252

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151158 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73790

African (AFR) AF: 0.0000243 AC: 1 AN: 41234

American (AMR) AF: 0.00 AC: 0 AN: 14892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.2
DANN	Benign	0.90
PhyloP100		-0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs397515531; hg19: chr6-32007325; COSMIC: COSV64482730; COSMIC: COSV64482730;