6-32038472-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000500.9(CYP21A2):c.50G>T(p.Arg17Leu) 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 benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R17C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.115

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1712288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.50G>T	p.Arg17Leu	missense_variant	1/10	ENST00000644719.2
CYP21A2	NM_001128590.4	c.50G>T	p.Arg17Leu	missense_variant	1/9
CYP21A2	NM_001368143.2	c.-375G>T		5_prime_UTR_variant	1/10
CYP21A2	NM_001368144.2	c.-285G>T		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.50G>T	p.Arg17Leu	missense_variant	1/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1424774 Hom.: 0 Cov.: 108 AF XY: 0.00 AC XY: 0 AN XY: 705652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Medical University Innsbruck

May 24, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	12
Dann	Benign	0.93
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.037	N
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;.;N;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.28	T;.;T;T;T;.
Sift4G	Benign	0.18	T;.;D;D;T;.
Polyphen		0.011	B;B;.;.;.;B
Vest4		0.30
MutPred		0.60		Loss of MoRF binding (P = 0.0042);Loss of MoRF binding (P = 0.0042);Loss of MoRF binding (P = 0.0042);Loss of MoRF binding (P = 0.0042);Loss of MoRF binding (P = 0.0042);Loss of MoRF binding (P = 0.0042);
MVP		0.93
MPC		2.2
ClinPred		0.77	D
GERP RS		-0.98
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs1185695713; hg19: chr6-32006249;