rs6471

Variant names:

• chr6-32040110-G-C
• rs6471
• NM_000500.9:c.844G>C
• CYP21A2 p.Val282Leu

Your query was ambiguous. Multiple possible variants found:

• chr6-32040110-G-C
• chr6-32040110-G-T
• chr6-32040110-G-A

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019): 12P and 0B. PS1_Very_StrongPM1PM2

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 is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Adrenal hyperplasia 3 (AH3).

• 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: 287 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: Laboratory for Molecular Medicine, Myriad Women's Health, Labcorp Genetics (formerly Invitae)
• 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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 12 points.

• PS1: Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 0 benign (OR vs. background: 25.0).
• PM2: Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (base 0.001, raised to 0.005 by highest known P/LP ClinVar AF 0.00716) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.844G>C	p.Val282Leu	missense	Exon 7 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.754G>C	p.Val252Leu	missense	Exon 6 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.439G>C	p.Val147Leu	missense	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.844G>C	p.Val282Leu	missense	Exon 7 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.880G>C	p.Val294Leu	missense	Exon 7 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.853G>C	p.Val285Leu	missense	Exon 7 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-0.93	T
PhyloP100		2.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.32
Sift	Benign	0.61	T
Sift4G	Benign	0.41	T
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6471;

hg19: chr6-32007887;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar