chr6-32039426-T-A

Variant names:

• chr6-32039426-T-A
• rs6475
• NM_000500.9:c.518T>A
• CYP21A2 p.Ile173Asn

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PS3 PM1 PP2 PP5_Very_Strong BP4

The NM_000500.9(CYP21A2):​c.518T>A​(p.Ile173Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 151,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001482475: Experimental studies have shown that this variant results in abnormal protein function (Tusie-Luna et al., 1990" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00049 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26 U:1 O:1
• Conservation: PhyloP100: 2.91
• Publications: 115 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: Laboratory for Molecular Medicine, Myriad Women's Health, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001482475: Experimental studies have shown that this variant results in abnormal protein function (Tusie-Luna et al., 1990;PMID: 2249999, Chiou et al., 1990;PMID: 2303461, Brønstad et al., 2014;PMID: 24671123).; SCV002059027: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24671123)."; SCV005416768: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006333643: Experimental evidence shows an impact on protein function, and demonstrated severely reduced enzyme activity (Xu C, et al. 2019).; SCV000841745: Experiments demonstrate this variant results in dramatically reduced enzymatic activity (PMID: 2249999, 24667412, 24671123).; SCV001469964: "In addition, experimental studies indicate this variant is damaging to protein function (PMIDs: 2249999 (1990), 24667412 (2014), 24671123 (2014))."; SCV003252584: Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 2249999, 30968594).; SCV003922699: Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely reduced enzyme activity (e.g. Tusie-Luna_1990, Chiou_1990, Xu_2019).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000500.9
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.
• PP5: Variant 6-32039426-T-A is Pathogenic according to our data. Variant chr6-32039426-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36651677). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000500.9. 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.518T>A	p.Ile173Asn	missense	Exon 4 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.428T>A	p.Ile143Asn	missense	Exon 3 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.113T>A	p.Ile38Asn	missense	Exon 4 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.518T>A	p.Ile173Asn	missense	Exon 4 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.518T>A	p.Ile173Asn	missense	Exon 4 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.518T>A	p.Ile173Asn	missense	Exon 4 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 151628 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000481 AC: 120 AN: 249434 AF XY: 0.000378

Gnomad AFR exome AF: 0.000376

Gnomad AMR exome AF: 0.000466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000819

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.000492

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000492 AC: 718 AN: 1457878 Hom.: 3 Cov.: 58 AF XY: 0.000483 AC XY: 350 AN XY: 725184

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

African (AFR) AF: 0.000300 AC: 10 AN: 33388

American (AMR) AF: 0.000494 AC: 22 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26046

East Asian (EAS) AF: 0.000908 AC: 36 AN: 39634

South Asian (SAS) AF: 0.000500 AC: 43 AN: 86016

European-Finnish (FIN) AF: 0.00220 AC: 117 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000406 AC: 450 AN: 1109024

Other (OTH) AF: 0.000531 AC: 32 AN: 60246

⚠️ 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: 0.00119 AC: 180 AN: 151748 Hom.: 0 Cov.: 31 AF XY: 0.00128 AC XY: 95 AN XY: 74224

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

African (AFR) AF: 0.00104 AC: 43 AN: 41432

American (AMR) AF: 0.00157 AC: 24 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5162

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10574

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

European-Non Finnish (NFE) AF: 0.00108 AC: 73 AN: 67738

Other (OTH) AF: 0.000474 AC: 1 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: 0.000750 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	1	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (19)
7	-	-	not provided (7)
1	-	-	Congenital adrenal hyperplasia (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.38	D
PhyloP100		2.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.017	D
gMVP		0.94
Mutation Taster		=2/98	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6475;

hg19: chr6-32007203;

COSMIC: COSV64482986;

COSMIC: COSV64482986;