6-32038462-G-T

Variant names:

• chr6-32038462-G-T
• rs764636694
• NM_000500.9:c.40G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_000500.9(CYP21A2):​c.40G>T​(p.Ala14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000766 in 1,566,912 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (1 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.40
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, 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: Likely_benign. The variant received -3 ACMG points.

• 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=0.03880465).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.40G>T	p.Ala14Ser	missense	Exon 1 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.40G>T	p.Ala14Ser	missense	Exon 1 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-385G>T		5_prime_UTR	Exon 1 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.40G>T	p.Ala14Ser	missense	Exon 1 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.40G>T	p.Ala14Ser	missense	Exon 1 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.40G>T	p.Ala14Ser	missense	Exon 1 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000230 AC: 40 AN: 173828 AF XY: 0.000286

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000144

Gnomad OTH exome AF: 0.000211

GnomAD4 exome AF: 0.0000827 AC: 117 AN: 1414656 Hom.: 1 Cov.: 103 AF XY: 0.000119 AC XY: 83 AN XY: 699566

African (AFR) AF: 0.00 AC: 0 AN: 32104

American (AMR) AF: 0.00 AC: 0 AN: 38144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25406

East Asian (EAS) AF: 0.00 AC: 0 AN: 37286

South Asian (SAS) AF: 0.00128 AC: 104 AN: 81368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1087344

Other (OTH) AF: 0.000188 AC: 11 AN: 58556

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74434

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000230 AC: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.94	T
PhyloP100		2.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.22
Sift	Benign	0.096	T
Sift4G	Uncertain	0.022	D
Polyphen		0.94	P
Vest4		0.28
MutPred		0.55		Loss of helix (P = 0.0304)
MVP		0.92
MPC		1.8
ClinPred		0.078	T
GERP RS		2.2
PromoterAI		-0.0062	Neutral
gMVP		0.27
Mutation Taster		=95/5	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: rs764636694; hg19: chr6-32006239;