rs767333157

Variant names:

• chr6-32040952-C-T
• rs767333157
• NM_000500.9:c.1306C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32040952-C-T
• chr6-32040952-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_000500.9(CYP21A2):​c.1306C>T​(p.Arg436Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.448
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.015557289).
• BP6: Variant 6-32040952-C-T is Benign according to our data. Variant chr6-32040952-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193595.

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.1306C>T	p.Arg436Cys	missense	Exon 10 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.1216C>T	p.Arg406Cys	missense	Exon 9 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.901C>T	p.Arg301Cys	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.1306C>T	p.Arg436Cys	missense	Exon 10 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.1342C>T	p.Arg448Cys	missense	Exon 10 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.1315C>T	p.Arg439Cys	missense	Exon 10 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.000889 AC: 134 AN: 150780 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00214 AC: 287 AN: 134056 AF XY: 0.00187

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.0000817

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0259

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000489

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000839 AC: 868 AN: 1034512 Hom.: 0 Cov.: 15 AF XY: 0.000789 AC XY: 414 AN XY: 524402

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

African (AFR) AF: 0.000110 AC: 3 AN: 27290

American (AMR) AF: 0.0000567 AC: 2 AN: 35266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23202

East Asian (EAS) AF: 0.0193 AC: 651 AN: 33714

South Asian (SAS) AF: 0.000148 AC: 11 AN: 74188

European-Finnish (FIN) AF: 0.0000259 AC: 1 AN: 38668

Middle Eastern (MID) AF: 0.000277 AC: 1 AN: 3614

European-Non Finnish (NFE) AF: 0.000162 AC: 122 AN: 751790

Other (OTH) AF: 0.00165 AC: 77 AN: 46780

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000888 AC: 134 AN: 150896 Hom.: 0 Cov.: 33 AF XY: 0.000733 AC XY: 54 AN XY: 73630

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

African (AFR) AF: 0.000217 AC: 9 AN: 41492

American (AMR) AF: 0.00125 AC: 19 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.0194 AC: 95 AN: 4892

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67358

Other (OTH) AF: 0.00191 AC: 4 AN: 2094

⚠️ 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

ExAC AF: 0.000313 AC: 15

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.28	N
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.21	D
PhyloP100		0.45
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.92		Loss of methylation at R436 (P = 0.0139)
MVP		0.93
MPC		3.5
ClinPred		0.16	T
GERP RS		4.5
gMVP		0.68
Mutation Taster		=31/69	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: rs767333157; hg19: chr6-32008729; COSMIC: COSV64478243; COSMIC: COSV64478243;