NM_000500.9:c.747C>T

Variant names:

• chr6-32040013-C-T
• rs6477
• NM_000500.9:c.747C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000500.9(CYP21A2):​c.747C>T​(p.Leu249Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,420,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L249L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220
• 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP7: Synonymous conserved (PhyloP=0.022 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000500.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.747C>T	p.Leu249Leu	synonymous	Exon 7 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.657C>T	p.Leu219Leu	synonymous	Exon 6 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.342C>T	p.Leu114Leu	synonymous	Exon 7 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.747C>T	p.Leu249Leu	synonymous	Exon 7 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.783C>T	p.Leu261Leu	synonymous	Exon 7 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.756C>T	p.Leu252Leu	synonymous	Exon 7 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000929 AC: 2 AN: 215192 AF XY: 0.0000173

Gnomad AFR exome AF: 0.0000726

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000608

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1420286 Hom.: 0 Cov.: 69 AF XY: 0.00000142 AC XY: 1 AN XY: 706404

African (AFR) AF: 0.00 AC: 0 AN: 32426

American (AMR) AF: 0.00 AC: 0 AN: 43122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.0000514 AC: 2 AN: 38896

South Asian (SAS) AF: 0.00 AC: 0 AN: 83492

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5092

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1081272

Other (OTH) AF: 0.00 AC: 0 AN: 58778

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		0.022

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6477; hg19: chr6-32007790;