rs6464

Variant names:

• chr6-32038560-C-A
• rs6464
• NM_000500.9:c.138C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32038560-C-A
• chr6-32038560-C-G
• chr6-32038560-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000500.9(CYP21A2):​c.138C>A​(p.Pro46Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 150,242 control chromosomes in the GnomAD database, including 36,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (36743 hom., cov: 29)
  • Exomes 𝑓: 0.70 (340401 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.442
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 6-32038560-C-A is Benign according to our data. Variant chr6-32038560-C-A is described in ClinVar as Benign. ClinVar VariationId is 256287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.442 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.721 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.138C>A	p.Pro46Pro	synonymous	Exon 1 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.138C>A	p.Pro46Pro	synonymous	Exon 1 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-287C>A		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.138C>A	p.Pro46Pro	synonymous	Exon 1 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.138C>A	p.Pro46Pro	synonymous	Exon 1 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.138C>A	p.Pro46Pro	synonymous	Exon 1 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.709 AC: 106472 AN: 150122 Hom.: 36709 Cov.: 29

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.904

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.697

GnomAD2 exomes AF: 0.689 AC: 146582 AN: 212814 AF XY: 0.685

Gnomad AFR exome AF: 0.659

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.745

Gnomad EAS exome AF: 0.636

Gnomad FIN exome AF: 0.727

Gnomad NFE exome AF: 0.678

Gnomad OTH exome AF: 0.674

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.700 AC: 1010880 AN: 1444304 Hom.: 340401 Cov.: 96 AF XY: 0.698 AC XY: 500628 AN XY: 717004

African (AFR) AF: 0.679 AC: 22380 AN: 32950

American (AMR) AF: 0.770 AC: 32849 AN: 42644

Ashkenazi Jewish (ASJ) AF: 0.740 AC: 19085 AN: 25794

East Asian (EAS) AF: 0.615 AC: 23982 AN: 39022

South Asian (SAS) AF: 0.642 AC: 54006 AN: 84172

European-Finnish (FIN) AF: 0.730 AC: 37808 AN: 51760

Middle Eastern (MID) AF: 0.681 AC: 3812 AN: 5596

European-Non Finnish (NFE) AF: 0.703 AC: 775502 AN: 1102702

Other (OTH) AF: 0.695 AC: 41456 AN: 59664

GnomAD4 genome AF: 0.709 AC: 106560 AN: 150242 Hom.: 36743 Cov.: 29 AF XY: 0.708 AC XY: 51976 AN XY: 73366

African (AFR) AF: 0.691 AC: 28202 AN: 40804

American (AMR) AF: 0.733 AC: 11062 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2569 AN: 3460

East Asian (EAS) AF: 0.691 AC: 3425 AN: 4960

South Asian (SAS) AF: 0.664 AC: 3178 AN: 4784

European-Finnish (FIN) AF: 0.761 AC: 7929 AN: 10426

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.708 AC: 47706 AN: 67424

Other (OTH) AF: 0.700 AC: 1465 AN: 2092

Alfa AF: 0.545 Hom.: 3400

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	-0.68
CADD	Benign	5.0
DANN	Benign	0.83
PhyloP100		0.44
PromoterAI		-0.0034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs6464; hg19: chr6-32006337; COSMIC: COSV64481742; COSMIC: COSV64481742;