rs6445

Variant names:

• chr6-32041006-C-T
• rs6445
• NM_000500.9:c.1360C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 13P and 2B. PS3 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_000500.9(CYP21A2):​c.1360C>T​(p.Pro454Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,223,580 control chromosomes in the GnomAD database, including 3 homozygotes. 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: "SCV000494248: Furthermore, in vitro functional assays in multiple studies demonstrated that, compared to the wild-type enzyme, this variant had decreased activity on both the 17-OHP and progesterone substrates (Nikoshkov et al., 1997, Barbaro et al., 2015)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (3 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:31 O:1
• Conservation: PhyloP100: 0.697
• Publications: 46 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]

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNXB Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, PanelApp Australia
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000494248: Furthermore, in vitro functional assays in multiple studies demonstrated that, compared to the wild-type enzyme, this variant had decreased activity on both the 17-OHP and progesterone substrates (Nikoshkov et al., 1997, Barbaro et al., 2015).; SCV001142355: "In vitro functional assays in multiple studies demonstrated that, compared to the wild-type enzyme, this variant had decreased activity on both the 17-OHP and progesterone substrates." PMID:24953648; SCV002556234: At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Helmberg_1992, Nikoshkov_1997, Soardi_2008).; SCV002572784: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID:24953648; SCV000841733: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 24953648); SCV002047337: Functional evidence suggests that this variant may impact protein function. PMID: 12788866 (2003) PMID: 18381579 (2008); SCV002126037: Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 18381579, 24953648, 30968594).
• 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 6-32041006-C-T is Pathogenic according to our data. Variant chr6-32041006-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013331294). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1360C>T	p.Pro454Ser	missense	Exon 10 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.1270C>T	p.Pro424Ser	missense	Exon 9 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.955C>T	p.Pro319Ser	missense	Exon 10 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.1360C>T	p.Pro454Ser	missense	Exon 10 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.1396C>T	p.Pro466Ser	missense	Exon 10 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.1369C>T	p.Pro457Ser	missense	Exon 10 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 771 AN: 151528 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00172

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00899

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00460 AC: 633 AN: 137706 AF XY: 0.00448

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00320

Gnomad ASJ exome AF: 0.000365

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00902

Gnomad OTH exome AF: 0.00386

GnomAD4 exome AF: 0.00645 AC: 6916 AN: 1071934 Hom.: 3 Cov.: 16 AF XY: 0.00641 AC XY: 3469 AN XY: 541524

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

African (AFR) AF: 0.00106 AC: 30 AN: 28422

American (AMR) AF: 0.00279 AC: 99 AN: 35448

Ashkenazi Jewish (ASJ) AF: 0.000471 AC: 11 AN: 23366

East Asian (EAS) AF: 0.00 AC: 0 AN: 34722

South Asian (SAS) AF: 0.000732 AC: 55 AN: 75106

European-Finnish (FIN) AF: 0.00219 AC: 75 AN: 34300

Middle Eastern (MID) AF: 0.00192 AC: 7 AN: 3640

European-Non Finnish (NFE) AF: 0.00811 AC: 6396 AN: 788760

Other (OTH) AF: 0.00504 AC: 243 AN: 48170

⚠️ 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: 0.00508 AC: 771 AN: 151646 Hom.: 0 Cov.: 33 AF XY: 0.00463 AC XY: 343 AN XY: 74058

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

African (AFR) AF: 0.00166 AC: 69 AN: 41538

American (AMR) AF: 0.00334 AC: 51 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00172 AC: 18 AN: 10476

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

European-Non Finnish (NFE) AF: 0.00900 AC: 609 AN: 67698

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

⚠️ 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: 0.00775 Hom.: 0

ExAC AF: 0.000962 AC: 85

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (16)
13	-	-	not provided (13)
1	-	-	Congenital lipoid adrenal hyperplasia due to STAR deficency (1)
1	-	-	CYP21A2-related disorder (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.47	T
PhyloP100		0.70
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.70
MVP		0.71
MPC		0.032
ClinPred		0.036	T
GERP RS		3.7
gMVP		0.75
Mutation Taster		=16/84	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: rs6445; hg19: chr6-32008783; COSMIC: COSV64482528; COSMIC: COSV64482528;