6-32038514-C-T

Variant names:

• chr6-32038514-C-T
• rs9378251
• NM_000500.9:c.92C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001368143.2(CYP21A2):​c.-333C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,607,244 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: CYP21A2 NM_001368143.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 2.34
• Publications: 181 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: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 6-32038514-C-T is Pathogenic according to our data. Variant chr6-32038514-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.92C>T	p.Pro31Leu	missense	Exon 1 of 10	NP_000491.4
	CYP21A2	NM_001368143.2		c.-333C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001355072.1
	CYP21A2	NM_001368144.2		c.-243C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001355073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.92C>T	p.Pro31Leu	missense	Exon 1 of 10	ENSP00000496625.1
	CYP21A2	ENST00000960600.1		c.92C>T	p.Pro31Leu	missense	Exon 1 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.92C>T	p.Pro31Leu	missense	Exon 1 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 152008 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.0000916 AC: 22 AN: 240194 AF XY: 0.0000690

Gnomad AFR exome AF: 0.000334

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000934

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1455118 Hom.: 1 Cov.: 107 AF XY: 0.0000899 AC XY: 65 AN XY: 723376

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000180 AC: 6 AN: 33290

American (AMR) AF: 0.000114 AC: 5 AN: 43958

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25978

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39538

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85382

European-Finnish (FIN) AF: 0.000133 AC: 7 AN: 52532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000956 AC: 106 AN: 1108550

Other (OTH) AF: 0.000133 AC: 8 AN: 60138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152126 Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74378

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000818 AC: 34 AN: 41544

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67930

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000528 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (12)
6	-	-	not provided (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Benign	0.085	T
Eigen	Benign	0.020
Eigen_PC	Benign	-0.0015
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.38	T
PhyloP100		2.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.56
Sift	Benign	0.92	T
Sift4G	Uncertain	0.060	T
Polyphen		0.20	B
Vest4		0.56
MutPred		0.94		Gain of MoRF binding (P = 0.0597)
MVP		0.85
MPC		2.2
ClinPred		0.053	T
GERP RS		3.6
PromoterAI		0.021	Neutral
gMVP		0.73
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs9378251; hg19: chr6-32006291; COSMIC: COSV100926680; COSMIC: COSV100926680;