6-32040110-G-C

Variant names:

• chr6-32040110-G-C
• rs6471
• NM_000500.9:c.844G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1_Very_Strong PM2 PP2 PP3

The NM_000500.9(CYP21A2):​c.844G>C​(p.Val282Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.60
• Publications: 280 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: Pathogenic. The variant received 12 ACMG points.

• PS1: Transcript NM_000500.9 (CYP21A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.844G>C	p.Val282Leu	missense_variant	Exon 7 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.754G>C	p.Val252Leu	missense_variant	Exon 6 of 9		NP_001122062.3
CYP21A2	NM_001368143.2	c.439G>C	p.Val147Leu	missense_variant	Exon 7 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.439G>C	p.Val147Leu	missense_variant	Exon 6 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.844G>C	p.Val282Leu	missense_variant	Exon 7 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Benign	0.054
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.57	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.93	T
PhyloP100		2.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.90	N;.;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.61	T;.;T;.
Sift4G	Benign	0.41	T;.;T;.
Polyphen		0.93	P;P;.;P
Vest4		0.88
MutPred		0.86		Gain of disorder (P = 0.1696);Gain of disorder (P = 0.1696);.;Gain of disorder (P = 0.1696);
MVP		0.91
MPC		1.2
ClinPred		0.80	D
GERP RS		4.0
gMVP		0.60
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs6471; hg19: chr6-32007887;