rs397515531

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-32039548-C-A
• chr6-32039548-C-G
• chr6-32039548-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000500.9(CYP21A2):​c.552C>A​(p.Asp184Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.725
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.552C>A	p.Asp184Glu	missense_variant, splice_region_variant	Exon 5 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.462C>A	p.Asp154Glu	missense_variant, splice_region_variant	Exon 4 of 9		NP_001122062.3
CYP21A2	NM_001368143.2	c.147C>A	p.Asp49Glu	missense_variant, splice_region_variant	Exon 5 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.147C>A	p.Asp49Glu	missense_variant, splice_region_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>A	p.Asp184Glu	missense_variant, splice_region_variant	Exon 5 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432982 Hom.: 0 Cov.: 58 AF XY: 0.00000141 AC XY: 1 AN XY: 710300

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

American (AMR) AF: 0.00 AC: 0 AN: 40034

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 38666

South Asian (SAS) AF: 0.0000120 AC: 1 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: 0.00 AC: 0 AN: 1096208

Other (OTH) AF: 0.00 AC: 0 AN: 59252

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.73
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0033	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.72
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.21	N;.;N;.
REVEL	Benign	0.027
Sift	Benign	1.0	T;.;T;.
Sift4G	Benign	1.0	T;.;T;.
Polyphen		0.0010	B;B;.;B
Vest4		0.069
MutPred		0.44		Loss of ubiquitination at K183 (P = 0.0962);Loss of ubiquitination at K183 (P = 0.0962);.;Loss of ubiquitination at K183 (P = 0.0962);
MVP		0.39
MPC		0.43
ClinPred		0.032	T
GERP RS		-3.4
gMVP		0.076
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: 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;