rs184649564

Variant names:

• chr6-32041085-G-T
• rs184649564
• NM_000500.9:c.1439G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32041085-G-T
• chr6-32041085-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1 PM2 PP2 BP4_Strong BP6

The NM_000500.9(CYP21A2):​c.1439G>T​(p.Arg480Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,571,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.139
• Publications: 8 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000500.9
• PM2: Variant has high frequency in the AFR (0.0563) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 1).
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004269749).
• BP6: Variant 6-32041085-G-T is Benign according to our data. Variant chr6-32041085-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445854.

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.1439G>T	p.Arg480Leu	missense	Exon 10 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.1349G>T	p.Arg450Leu	missense	Exon 9 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.1034G>T	p.Arg345Leu	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.1439G>T	p.Arg480Leu	missense	Exon 10 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.1475G>T	p.Arg492Leu	missense	Exon 10 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.1448G>T	p.Arg483Leu	missense	Exon 10 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2579 AN: 150916 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00755

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.0174

GnomAD2 exomes AF: 0.00491 AC: 1047 AN: 213178 AF XY: 0.00392

Gnomad AFR exome AF: 0.0652

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.00223

GnomAD4 exome AF: 0.00179 AC: 2547 AN: 1420082 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 1111 AN XY: 705868

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

African (AFR) AF: 0.0584 AC: 1911 AN: 32698

American (AMR) AF: 0.00451 AC: 193 AN: 42832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.00 AC: 0 AN: 39126

South Asian (SAS) AF: 0.000571 AC: 48 AN: 84104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41336

Middle Eastern (MID) AF: 0.00573 AC: 25 AN: 4362

European-Non Finnish (NFE) AF: 0.0000926 AC: 101 AN: 1091268

Other (OTH) AF: 0.00456 AC: 269 AN: 59020

⚠️ 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: 0.0171 AC: 2581 AN: 151034 Hom.: 1 Cov.: 33 AF XY: 0.0166 AC XY: 1226 AN XY: 73848

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

African (AFR) AF: 0.0588 AC: 2405 AN: 40886

American (AMR) AF: 0.00754 AC: 115 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3362

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

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

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67806

Other (OTH) AF: 0.0173 AC: 36 AN: 2086

⚠️ 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: 0.00125 Hom.: 0

ESP6500AA AF: 0.0440 AC: 118

ESP6500EA AF: 0.000595 AC: 3

ExAC AF: 0.00482 AC: 574

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	2	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.92
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.22	N
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.85	T
PhyloP100		-0.14
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.32	T
Sift4G	Benign	0.39	T
Polyphen		0.31	B
Vest4		0.70
MVP		0.46
MPC		0.017
ClinPred		0.016	T
GERP RS		0.38
gMVP		0.66
Mutation Taster		=36/64	disease causing

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: rs184649564; hg19: chr6-32008862; COSMIC: COSV99056687; COSMIC: COSV99056687;