rs6467

chr6-32039081-C-Achr6-32039081-C-Gchr6-32039081-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000500.9(CYP21A2):c.293-13C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 151,196 control chromosomes in the GnomAD database, including 28,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28032 hom., cov: 29)
  • Exomes 𝑓: 0.60 (254518 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.233

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7294652E-6).
• BP6: Variant 6-32039081-C-A is Benign according to our data. Variant chr6-32039081-C-A is described in ClinVar as [Benign]. Clinvar id is 196278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039081-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.293-13C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000644719.2
CYP21A2	NM_001368143.2	c.-126C>A		5_prime_UTR_variant	3/10
CYP21A2	NM_001368144.2	c.-126C>A		5_prime_UTR_variant	2/9
CYP21A2	NM_001128590.4	c.203-13C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.293-13C>A		splice_polypyrimidine_tract_variant, intron_variant			NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.609 AC: 91969 AN: 151080 Hom.: 28000 Cov.: 29

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.711

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.644

GnomAD3 exomes AF: 0.637 AC: 141158 AN: 221616 Hom.: 44741 AF XY: 0.635 AC XY: 75748 AN XY: 119232

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.634

Gnomad SAS exome AF: 0.629

Gnomad FIN exome AF: 0.475

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.644

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.595 AC: 857154 AN: 1440498 Hom.: 254518 Cov.: 74 AF XY: 0.596 AC XY: 425953 AN XY: 714448

Gnomad4 AFR exome AF: 0.644

Gnomad4 AMR exome AF: 0.733

Gnomad4 ASJ exome AF: 0.647

Gnomad4 EAS exome AF: 0.658

Gnomad4 SAS exome AF: 0.616

Gnomad4 FIN exome AF: 0.471

Gnomad4 NFE exome AF: 0.588

Gnomad4 OTH exome AF: 0.601

GnomAD4 genome AF: 0.609 AC: 92050 AN: 151196 Hom.: 28032 Cov.: 29 AF XY: 0.605 AC XY: 44652 AN XY: 73832

Gnomad4 AFR AF: 0.636

Gnomad4 AMR AF: 0.711

Gnomad4 ASJ AF: 0.636

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.436

Gnomad4 NFE AF: 0.592

Gnomad4 OTH AF: 0.646

Alfa AF: 0.561 Hom.: 9188

Bravo AF: 0.636

TwinsUK AF: 0.614 AC: 2275

ALSPAC AF: 0.607 AC: 2338

ESP6500AA AF: 0.656 AC: 2883

ESP6500EA AF: 0.616 AC: 5296

ExAC AF: 0.608 AC: 73208

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 23, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2019	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.0
DANN	Benign	0.44
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	0.40	N
REVEL	Benign	0.034
Sift	Benign	0.31	T
Sift4G	Pathogenic	0.0	D
ClinPred		0.0018	T
GERP RS		-0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6467; hg19: chr6-32006858; COSMIC: COSV64479798; COSMIC: COSV64479798;