rs147821751

Positions:

• chr6-32039090-G-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002665
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.59

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 256290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039090-G-A is described in Lovd as [Likely_benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.293-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644719.2	NP_000491.4
CYP21A2	NM_001368143.2	c.-117G>A		5_prime_UTR_variant	3/10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-117G>A		5_prime_UTR_variant	2/9		NP_001355073.1
CYP21A2	NM_001128590.4	c.203-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001122062.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.293-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_000500.9	ENSP00000496625	P1

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

GnomAD3 exomes AF: 0.00329 AC: 761 AN: 231458 Hom.: 5 AF XY: 0.00363 AC XY: 453 AN XY: 124890

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 SAS exome AF: 0.00191

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

Gnomad4 AFR exome AF: 0.000484

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.00393

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00481

Gnomad4 NFE exome AF: 0.00355

Gnomad4 OTH exome AF: 0.00377

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

Gnomad4 AFR AF: 0.000642

Gnomad4 AMR AF: 0.00335

Gnomad4 ASJ AF: 0.00436

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00128

Gnomad4 FIN AF: 0.00450

Gnomad4 NFE AF: 0.00516

Gnomad4 OTH AF: 0.00672

Alfa AF: 0.00450 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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	0.98	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs147821751; hg19: chr6-32006867;