NM_000500.9:c.138C>G

Variant names:

• chr6-32038560-C-G
• rs6464
• NM_000500.9:c.138C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_000500.9(CYP21A2):​c.138C>G​(p.Pro46Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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. P46P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.442
• Publications: 15 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP7: Synonymous conserved (PhyloP=0.442 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.138C>G	p.Pro46Pro	synonymous	Exon 1 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.138C>G	p.Pro46Pro	synonymous	Exon 1 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-287C>G		5_prime_UTR	Exon 1 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.138C>G	p.Pro46Pro	synonymous	Exon 1 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.138C>G	p.Pro46Pro	synonymous	Exon 1 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.138C>G	p.Pro46Pro	synonymous	Exon 1 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150302 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1446538 Hom.: 0 Cov.: 96 AF XY: 0.00 AC XY: 0 AN XY: 718258

African (AFR) AF: 0.00 AC: 0 AN: 33004

American (AMR) AF: 0.00 AC: 0 AN: 42854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39182

South Asian (SAS) AF: 0.00 AC: 0 AN: 84422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103918

Other (OTH) AF: 0.00 AC: 0 AN: 59776

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150302 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73334

African (AFR) AF: 0.00 AC: 0 AN: 40754

American (AMR) AF: 0.00 AC: 0 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 4976

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67474

Other (OTH) AF: 0.00 AC: 0 AN: 2074

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.9
DANN	Benign	0.79
PhyloP100		0.44
PromoterAI		0.032	Neutral

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: rs6464; hg19: chr6-32006337;