rs6458

Variant names:

• chr6-32039847-A-G
• rs6458
• NM_000500.9:c.738+12A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000500.9(CYP21A2):​c.738+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,603,274 control chromosomes in the GnomAD database, including 12,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1808 hom., cov: 31)
  • Exomes 𝑓: 0.11 (10413 hom.)
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.57
• Publications: 6 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-32039847-A-G is Benign according to our data. Variant chr6-32039847-A-G is described in ClinVar as Benign. ClinVar VariationId is 256298.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.738+12A>G		intron_variant	Intron 6 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4	c.648+12A>G		intron_variant	Intron 5 of 8		NP_001122062.3
CYP21A2	NM_001368143.2	c.333+12A>G		intron_variant	Intron 6 of 9		NP_001355072.1
CYP21A2	NM_001368144.2	c.333+12A>G		intron_variant	Intron 5 of 8		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.738+12A>G		intron_variant	Intron 6 of 9		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22251 AN: 151392 Hom.: 1800 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0700

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.197

GnomAD2 exomes AF: 0.131 AC: 31911 AN: 242802 AF XY: 0.135

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.0973

Gnomad FIN exome AF: 0.0718

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.115 AC: 166679 AN: 1451760 Hom.: 10413 Cov.: 80 AF XY: 0.119 AC XY: 85600 AN XY: 721856

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

African (AFR) AF: 0.223 AC: 7328 AN: 32906

American (AMR) AF: 0.132 AC: 5848 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5071 AN: 25880

East Asian (EAS) AF: 0.105 AC: 4150 AN: 39588

South Asian (SAS) AF: 0.242 AC: 20346 AN: 84198

European-Finnish (FIN) AF: 0.0752 AC: 4007 AN: 53256

Middle Eastern (MID) AF: 0.221 AC: 1231 AN: 5566

European-Non Finnish (NFE) AF: 0.100 AC: 110609 AN: 1106184

Other (OTH) AF: 0.135 AC: 8089 AN: 59962

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.147 AC: 22282 AN: 151514 Hom.: 1808 Cov.: 31 AF XY: 0.148 AC XY: 10926 AN XY: 74036

African (AFR) AF: 0.215 AC: 8867 AN: 41244

American (AMR) AF: 0.172 AC: 2616 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 711 AN: 3448

East Asian (EAS) AF: 0.100 AC: 515 AN: 5138

South Asian (SAS) AF: 0.216 AC: 1028 AN: 4768

European-Finnish (FIN) AF: 0.0700 AC: 742 AN: 10606

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.108 AC: 7309 AN: 67828

Other (OTH) AF: 0.194 AC: 407 AN: 2094

Alfa AF: 0.0739 Hom.: 134

Bravo AF: 0.158

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.39
DANN	Benign	0.71
PhyloP100		-1.6
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: rs6458; hg19: chr6-32007624; COSMIC: COSV64483665; COSMIC: COSV64483665;