rs6467

Variant names:

• chr6-32039081-C-A
• rs6467
• NM_000500.9:c.293-13C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32039081-C-A
• chr6-32039081-C-G
• chr6-32039081-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000500.9(CYP21A2):​c.293-13C>A variant causes a 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.61 (28032 hom., cov: 29)
  • Exomes 𝑓: 0.60 (254518 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:9
• Conservation: PhyloP100: -0.233
• Publications: 78 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=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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196278.
• 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 rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.293-13C>A		intron_variant	Intron 2 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001368143.2	c.-126C>A		5_prime_UTR_variant	Exon 3 of 10		NP_001355072.1
CYP21A2	NM_001368144.2	c.-126C>A		5_prime_UTR_variant	Exon 2 of 9		NP_001355073.1
CYP21A2	NM_001128590.4	c.203-13C>A		intron_variant	Intron 1 of 8		NP_001122062.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.293-13C>A		intron_variant	Intron 2 of 9		NM_000500.9	ENSP00000496625.1

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

GnomAD2 exomes AF: 0.637 AC: 141158 AN: 221616 AF XY: 0.635

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 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

African (AFR) AF: 0.644 AC: 21316 AN: 33106

American (AMR) AF: 0.733 AC: 31315 AN: 42702

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 16619 AN: 25696

East Asian (EAS) AF: 0.658 AC: 25592 AN: 38918

South Asian (SAS) AF: 0.616 AC: 51270 AN: 83168

European-Finnish (FIN) AF: 0.471 AC: 24176 AN: 51358

Middle Eastern (MID) AF: 0.684 AC: 3717 AN: 5438

European-Non Finnish (NFE) AF: 0.588 AC: 647335 AN: 1100550

Other (OTH) AF: 0.601 AC: 35814 AN: 59562

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

African (AFR) AF: 0.636 AC: 26219 AN: 41200

American (AMR) AF: 0.711 AC: 10828 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2204 AN: 3466

East Asian (EAS) AF: 0.632 AC: 3191 AN: 5052

South Asian (SAS) AF: 0.597 AC: 2854 AN: 4778

European-Finnish (FIN) AF: 0.436 AC: 4563 AN: 10458

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.592 AC: 40080 AN: 67728

Other (OTH) AF: 0.646 AC: 1354 AN: 2096

Alfa AF: 0.569 Hom.: 10792

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:1 Benign:3

Dec 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 12, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The intron variant c.293-13C>A variant in CYP21A2 gene, also known as In2G variant, represents the most common CYP21A2 gene changes related to the classic 21OHD form. The In2G variant is frequent in patients with 21OHD (Kocova et al., 2022). The c.293-13C>A variant is present with allele frequency of 0.63% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Benign. It normally causes severe disease; however, the clinical presentation can vary from the SW form, through the SV form and rarely the NC form. Thus, there is a difference in the severity of 21OHD within group A. The mechanism underlying the variation in the clinical phenotype of the In2G variant was widely discussed. The most accredited hypothesis is that a small number of transcripts avoid aberrant splicing, providing a small amount of the 21- hydroxylase enzyme, which is sufficient for a milder clinical presentation of the disease (Kocova et al., 2022). For these reasons, this variant has been classified as Pathogenic. -

not specified Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 23, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
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
PhyloP100		-0.23
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
Mutation Taster		=47/41	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs6467; hg19: chr6-32006858; COSMIC: COSV64479798; COSMIC: COSV64479798;