rs6473

chr6-32041127-G-Achr6-32041127-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000500.9(CYP21A2):c.1481G>A(p.Ser494Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S494S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (261 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.227

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006213218).
• BP6: Variant 6-32041127-G-A is Benign according to our data. Variant chr6-32041127-G-A is described in ClinVar as [Benign]. Clinvar id is 193596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32041127-G-A is described in Lovd as [Benign]. Variant chr6-32041127-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.1481G>A	p.Ser494Asn	missense_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2			downstream_gene_variant		ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.1481G>A	p.Ser494Asn	missense_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2			downstream_gene_variant			NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 782 AN: 138106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0291

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00716

Gnomad EAS AF: 0.00167

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.00771

Gnomad MID AF: 0.0109

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.00738

GnomAD3 exomes AF: 0.000375 AC: 89 AN: 237558 Hom.: 6 AF XY: 0.000339 AC XY: 44 AN XY: 129898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.000737

Gnomad EAS exome AF: 0.000169

Gnomad SAS exome AF: 0.000501

Gnomad FIN exome AF: 0.000112

Gnomad NFE exome AF: 0.000529

Gnomad OTH exome AF: 0.000516

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00301 AC: 4166 AN: 1383480 Hom.: 261 Cov.: 33 AF XY: 0.00309 AC XY: 2125 AN XY: 687484

Gnomad4 AFR exome AF: 0.00142

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.000721

Gnomad4 SAS exome AF: 0.00565

Gnomad4 FIN exome AF: 0.00553

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00413

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00566 AC: 782 AN: 138240 Hom.: 0 Cov.: 33 AF XY: 0.00579 AC XY: 392 AN XY: 67722

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00496

Gnomad4 ASJ AF: 0.00716

Gnomad4 EAS AF: 0.00167

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00771

Gnomad4 NFE AF: 0.00697

Gnomad4 OTH AF: 0.00780

Alfa AF: 0.00676 Hom.: 8

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.46
Dann	Benign	0.60
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.021	N
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0062	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.50	N;.;N;.
REVEL	Benign	0.076
Sift	Benign	0.45	T;.;T;.
Sift4G	Benign	1.0	T;.;T;.
Polyphen		0.0030	B;B;.;B
Vest4		0.041
MVP		0.25
MPC		0.0098
ClinPred		0.0087	T
GERP RS		2.6
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs6473; hg19: chr6-32008904; COSMIC: COSV64473903; COSMIC: COSV64473903;