6-32038820-C-T

Variant names:

• chr6-32038820-C-T
• rs6462
• NM_000500.9:c.292+9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000500.9(CYP21A2):​c.292+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,378,688 control chromosomes in the GnomAD database, including 343,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (38407 hom., cov: 28)
  • Exomes 𝑓: 0.71 (305415 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-32038820-C-T is Benign according to our data. Variant chr6-32038820-C-T is described in ClinVar as Benign. ClinVar VariationId is 256289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

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.292+9C>T		intron	N/A	NP_000491.4
	CYP21A2	NM_001128590.4		c.202+196C>T		intron	N/A	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-133+9C>T		intron	N/A	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.292+9C>T		intron	N/A	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.292+9C>T		intron	N/A	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.292+9C>T		intron	N/A	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 107500 AN: 150210 Hom.: 38353 Cov.: 28

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.732

GnomAD2 exomes AF: 0.737 AC: 157800 AN: 214146 AF XY: 0.733

Gnomad AFR exome AF: 0.660

Gnomad AMR exome AF: 0.836

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 0.685

Gnomad FIN exome AF: 0.785

Gnomad NFE exome AF: 0.722

Gnomad OTH exome AF: 0.728

GnomAD4 exome AF: 0.707 AC: 868177 AN: 1228364 Hom.: 305415 Cov.: 20 AF XY: 0.708 AC XY: 437559 AN XY: 618032

African (AFR) AF: 0.661 AC: 20270 AN: 30674

American (AMR) AF: 0.822 AC: 32317 AN: 39322

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 17802 AN: 24030

East Asian (EAS) AF: 0.677 AC: 25412 AN: 37542

South Asian (SAS) AF: 0.696 AC: 55430 AN: 79670

European-Finnish (FIN) AF: 0.778 AC: 39529 AN: 50818

Middle Eastern (MID) AF: 0.686 AC: 3643 AN: 5312

European-Non Finnish (NFE) AF: 0.701 AC: 636836 AN: 908418

Other (OTH) AF: 0.703 AC: 36938 AN: 52578

GnomAD4 genome AF: 0.716 AC: 107613 AN: 150324 Hom.: 38407 Cov.: 28 AF XY: 0.717 AC XY: 52661 AN XY: 73464

African (AFR) AF: 0.666 AC: 27393 AN: 41112

American (AMR) AF: 0.793 AC: 11913 AN: 15032

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2634 AN: 3450

East Asian (EAS) AF: 0.685 AC: 3374 AN: 4924

South Asian (SAS) AF: 0.660 AC: 3142 AN: 4760

European-Finnish (FIN) AF: 0.793 AC: 8221 AN: 10366

Middle Eastern (MID) AF: 0.702 AC: 205 AN: 292

European-Non Finnish (NFE) AF: 0.720 AC: 48544 AN: 67394

Other (OTH) AF: 0.735 AC: 1534 AN: 2088

Alfa AF: 0.709 Hom.: 9402

Bravo AF: 0.717

Asia WGS AF: 0.745 AC: 2592 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.087
DANN	Benign	0.50
PhyloP100		-1.8
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6462; hg19: chr6-32006597;