6-32040072-G-A

Variant names:

• chr6-32040072-G-A
• rs6472
• NM_000500.9:c.806G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000500.9(CYP21A2):​c.806G>A​(p.Ser269Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S269T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.979
• Publications: 33 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000500.9
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08286491).

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.806G>A	p.Ser269Asn	missense	Exon 7 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.716G>A	p.Ser239Asn	missense	Exon 6 of 9	NP_001122062.3
	CYP21A2	NM_001368143.2		c.401G>A	p.Ser134Asn	missense	Exon 7 of 10	NP_001355072.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.806G>A	p.Ser269Asn	missense	Exon 7 of 10	ENSP00000496625.1
	CYP21A2	ENST00000435122.3	TSL:2	c.716G>A	p.Ser239Asn	missense	Exon 6 of 9	ENSP00000415043.2
	CYP21A2	ENST00000479074.5	TSL:3	n.864G>A		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000209 AC: 5 AN: 238976 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1448606 Hom.: 0 Cov.: 89 AF XY: 0.00000277 AC XY: 2 AN XY: 720994

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32864

American (AMR) AF: 0.000113 AC: 5 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101468

Other (OTH) AF: 0.00 AC: 0 AN: 59872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000386134), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 95

ExAC AF: 0.0000250 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.24
DANN	Benign	0.81
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.079	N
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.98
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.057
Sift	Benign	0.46	T
Sift4G	Benign	0.51	T
Polyphen		0.060	B
Vest4		0.040
MutPred		0.31		Loss of phosphorylation at S269 (P = 0.0384)
MVP		0.64
MPC		0.43
ClinPred		0.036	T
GERP RS		-3.0
gMVP		0.18
Mutation Taster		=93/7	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: rs6472; hg19: chr6-32007849;