rs186349245

Variant names:

• chr6-32038350-C-T
• rs186349245
• ENST00000960597.1:c.-73C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The ENST00000960597.1(CYP21A2):​c.-73C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,542,942 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (8 hom.)
• Consequence: CYP21A2 ENST00000960597.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000960597.1. 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.-73C>T		upstream_gene	N/A	NP_000491.4
	CYP21A2	NM_001128590.4		c.-73C>T		upstream_gene	N/A	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.-497C>T		upstream_gene	N/A	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000960597.1		c.-73C>T		5_prime_UTR	Exon 1 of 10	ENSP00000630656.1
	CYP21A2	ENST00000960598.1		c.-73C>T		5_prime_UTR	Exon 1 of 9	ENSP00000630657.1
	CYP21A2	ENST00000466779.5	TSL:5	n.-73C>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000417321.1	E7ERT7

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152126 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000679 AC: 944 AN: 1390698 Hom.: 8 Cov.: 30 AF XY: 0.000736 AC XY: 505 AN XY: 686222

African (AFR) AF: 0.00305 AC: 96 AN: 31516

American (AMR) AF: 0.000168 AC: 6 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.000795 AC: 20 AN: 25162

East Asian (EAS) AF: 0.0000840 AC: 3 AN: 35732

South Asian (SAS) AF: 0.00178 AC: 141 AN: 79132

European-Finnish (FIN) AF: 0.000139 AC: 6 AN: 43030

Middle Eastern (MID) AF: 0.00783 AC: 32 AN: 4086

European-Non Finnish (NFE) AF: 0.000511 AC: 551 AN: 1078586

Other (OTH) AF: 0.00154 AC: 89 AN: 57768

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152244 Hom.: 2 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74446

African (AFR) AF: 0.000385 AC: 16 AN: 41544

American (AMR) AF: 0.000458 AC: 7 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000638

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	CYP21A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.4
DANN	Benign	0.85
PhyloP100		0.0020
PromoterAI		0.042	Neutral
Mutation Taster		=300/0	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: rs186349245; hg19: chr6-32006127;