NM_000500.9:c.293-4G>A

Variant names:

• chr6-32039090-G-A
• rs147821751
• NM_000500.9:c.293-4G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000500.9(CYP21A2):​c.293-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,594,004 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (31 hom.)
• Consequence: CYP21A2 NM_000500.9 splice_region, intron
• Scores: Splicing: ADA: 0.0002665
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.59
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008644223).
• BP6: Variant 6-32039090-G-A is Benign according to our data. Variant chr6-32039090-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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: NM_000500.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.293-4G>A		splice_region intron	N/A	NP_000491.4
	CYP21A2	NM_001368143.2		c.-117G>A		5_prime_UTR	Exon 3 of 10	NP_001355072.1
	CYP21A2	NM_001368144.2		c.-117G>A		5_prime_UTR	Exon 2 of 9	NP_001355073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.293-4G>A		splice_region intron	N/A	ENSP00000496625.1
	CYP21A2	ENST00000478281.5	TSL:4	c.322G>A	p.Ala108Thr	missense	Exon 3 of 4	ENSP00000419572.1
	CYP21A2	ENST00000466779.5	TSL:5	n.308G>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000417321.1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 510 AN: 148674 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00436

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.00450

Gnomad MID AF: 0.0258

Gnomad NFE AF: 0.00516

Gnomad OTH AF: 0.00680

GnomAD2 exomes AF: 0.00329 AC: 761 AN: 231458 AF XY: 0.00363

Gnomad AFR exome AF: 0.000488

Gnomad AMR exome AF: 0.00271

Gnomad ASJ exome AF: 0.00304

Gnomad EAS exome AF: 0.0000575

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00405

GnomAD4 exome AF: 0.00336 AC: 4853 AN: 1445214 Hom.: 31 Cov.: 76 AF XY: 0.00344 AC XY: 2466 AN XY: 717448

African (AFR) AF: 0.000484 AC: 16 AN: 33070

American (AMR) AF: 0.00327 AC: 142 AN: 43452

Ashkenazi Jewish (ASJ) AF: 0.00393 AC: 101 AN: 25714

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39044

South Asian (SAS) AF: 0.00177 AC: 149 AN: 84128

European-Finnish (FIN) AF: 0.00481 AC: 247 AN: 51402

Middle Eastern (MID) AF: 0.0107 AC: 60 AN: 5632

European-Non Finnish (NFE) AF: 0.00355 AC: 3912 AN: 1103128

Other (OTH) AF: 0.00377 AC: 225 AN: 59644

GnomAD4 genome AF: 0.00341 AC: 508 AN: 148790 Hom.: 2 Cov.: 31 AF XY: 0.00333 AC XY: 241 AN XY: 72384

African (AFR) AF: 0.000642 AC: 26 AN: 40524

American (AMR) AF: 0.00335 AC: 50 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 15 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 4906

South Asian (SAS) AF: 0.00128 AC: 6 AN: 4690

European-Finnish (FIN) AF: 0.00450 AC: 44 AN: 9788

Middle Eastern (MID) AF: 0.0207 AC: 6 AN: 290

European-Non Finnish (NFE) AF: 0.00516 AC: 347 AN: 67230

Other (OTH) AF: 0.00672 AC: 14 AN: 2082

Alfa AF: 0.00468 Hom.: 0

Bravo AF: 0.00314

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00318 AC: 386

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 25, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 15, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Jul 28, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYP21A2: BP4, BS2

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Benign:1

Jun 01, 2022

Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.53
DANN	Benign	0.81
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.6
PROVEAN	Benign	0.31	N
REVEL	Benign	0.020
Sift	Benign	0.31	T
Sift4G	Uncertain	0.024	D
MVP		0.46
ClinPred		0.0024	T
GERP RS		-6.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.020
SpliceAI score (max)		0.050		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: rs147821751; hg19: chr6-32006867; COSMIC: COSV108220858;