NM_000500.9:c.293-13C>T

Variant names:

• chr6-32039081-C-T
• rs6467
• NM_000500.9:c.293-13C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000500.9(CYP21A2):​c.293-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.233
• Publications: 78 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067373395).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.293-13C>T		intron	N/A	NP_000491.4
	CYP21A2	NM_001368143.2		c.-126C>T		5_prime_UTR	Exon 3 of 10	NP_001355072.1
	CYP21A2	NM_001368144.2		c.-126C>T		5_prime_UTR	Exon 2 of 9	NP_001355073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.293-13C>T		intron	N/A	ENSP00000496625.1
	CYP21A2	ENST00000960598.1		c.223C>T	p.Pro75Ser	missense	Exon 2 of 9	ENSP00000630657.1
	CYP21A2	ENST00000478281.5	TSL:4	c.313C>T	p.Pro105Ser	missense	Exon 3 of 4	ENSP00000419572.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151138 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 AF: 6.94e-7 AC: 1 AN: 1440708 Hom.: 0 Cov.: 74 AF XY: 0.00 AC XY: 0 AN XY: 714552

African (AFR) AF: 0.00 AC: 0 AN: 33108

American (AMR) AF: 0.00 AC: 0 AN: 42720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25696

East Asian (EAS) AF: 0.00 AC: 0 AN: 38922

South Asian (SAS) AF: 0.00 AC: 0 AN: 83180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100710

Other (OTH) AF: 0.00 AC: 0 AN: 59568

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151138 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73734

African (AFR) AF: 0.00 AC: 0 AN: 41098

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10462

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67758

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

Alfa AF: 0.00 Hom.: 10792

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.2
DANN	Benign	0.58
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.23
PROVEAN	Benign	0.30	N
REVEL	Benign	0.026
Sift	Benign	0.40	T
Sift4G	Pathogenic	0.0	D
MutPred		0.39		Loss of catalytic residue at P105 (P = 0.0082)
MVP		0.25
ClinPred		0.025	T
GERP RS		-0.59
Mutation Taster		=42/41	polymorphism

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: rs6467; hg19: chr6-32006858;