6-32039081-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP3 PP5

The NM_001368143.2(CYP21A2):​c.-126C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 151,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001451452: Functional studies in COS-7 cells showed absent CYP21A2 activity for this variant (Higashi et al. 1988)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0024 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_001368143.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:36 U:1 O:1
• Conservation: PhyloP100: -0.233
• Publications: 82 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001451452: Functional studies in COS-7 cells showed absent CYP21A2 activity for this variant (Higashi et al. 1988).; SCV001482472: This variant activates a cryptic upstream 3' splice acceptor site and causing aberrant splicing (New et al., 2013); SCV002818261: PS3; SCV003922698: At least one publication reports experimental evidence evaluating an impact on protein function, finding that COS cells transfected with the variant displayed undetectable steroid 21-hydroxylase activity (e.g., Higashi_1988).; SCV005086881: RNA studies have shown that this variant results in aberrant splicing which is predicted to cause a frameshift and a premature termination codon (PMID: 2845408); SCV005415903: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000741505: In an assay testing CYP21A2 function, this variant showed a functionally abnormal result (Higashi, 1988).; SCV000841739: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 2845408)
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 6-32039081-C-G is Pathogenic according to our data. Variant chr6-32039081-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12155.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368143.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.293-13C>G		intron	N/A	NP_000491.4
	CYP21A2	NM_001368143.2		c.-126C>G		5_prime_UTR	Exon 3 of 10	NP_001355072.1
	CYP21A2	NM_001368144.2		c.-126C>G		5_prime_UTR	Exon 2 of 9	NP_001355073.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.293-13C>G		intron	N/A	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960598.1		c.223C>G	p.Pro75Ala	missense	Exon 2 of 9	ENSP00000630657.1
	CYP21A2	ENST00000478281.5	TSL:4	c.313C>G	p.Pro105Ala	missense	Exon 3 of 4	ENSP00000419572.1	E7EVC0

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 327 AN: 151120 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00138

Gnomad SAS AF: 0.00272

Gnomad FIN AF: 0.000669

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00226 AC: 501 AN: 221616 AF XY: 0.00242

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00371

Gnomad EAS exome AF: 0.00210

Gnomad FIN exome AF: 0.000831

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00146

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00245 AC: 3525 AN: 1440550 Hom.: 6 Cov.: 74 AF XY: 0.00237 AC XY: 1691 AN XY: 714484

African (AFR) AF: 0.00151 AC: 50 AN: 33104

American (AMR) AF: 0.00199 AC: 85 AN: 42718

Ashkenazi Jewish (ASJ) AF: 0.00378 AC: 97 AN: 25694

East Asian (EAS) AF: 0.00247 AC: 96 AN: 38920

South Asian (SAS) AF: 0.00279 AC: 232 AN: 83176

European-Finnish (FIN) AF: 0.00107 AC: 55 AN: 51366

Middle Eastern (MID) AF: 0.00331 AC: 18 AN: 5438

European-Non Finnish (NFE) AF: 0.00249 AC: 2744 AN: 1100572

Other (OTH) AF: 0.00248 AC: 148 AN: 59562

GnomAD4 genome AF: 0.00216 AC: 327 AN: 151236 Hom.: 1 Cov.: 29 AF XY: 0.00207 AC XY: 153 AN XY: 73856

African (AFR) AF: 0.00182 AC: 75 AN: 41218

American (AMR) AF: 0.00158 AC: 24 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.00138 AC: 7 AN: 5058

South Asian (SAS) AF: 0.00272 AC: 13 AN: 4780

European-Finnish (FIN) AF: 0.000669 AC: 7 AN: 10462

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00263 AC: 178 AN: 67734

Other (OTH) AF: 0.00286 AC: 6 AN: 2096

Alfa AF: 0.000522 Hom.: 10792

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00234 AC: 9

ExAC AF: 0.00205 AC: 247

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
26	1	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (28)
7	-	-	not provided (7)
1	-	-	Congenital adrenal hyperplasia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.7
DANN	Benign	0.38
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.23
PROVEAN	Benign	0.10	N
REVEL	Benign	0.044
Sift	Benign	1.0	T
Sift4G	Pathogenic	0.0	D
MVP		0.25
ClinPred		0.0033	T
GERP RS		-0.59
Mutation Taster		=47/41	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.75		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6467; hg19: chr6-32006858;