rs6473

Variant names:

• chr6-32041127-G-A
• rs6473
• NM_000500.9:c.1481G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32041127-G-A
• chr6-32041127-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

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. 16/20 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:3
• Conservation: PhyloP100: -0.227
• Publications: 9 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
• 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: Benign. The variant received -11 ACMG points.

• 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=0.006213218).
• BP6: Variant 6-32041127-G-A is Benign according to our data. Variant chr6-32041127-G-A is described in ClinVar as Benign. ClinVar VariationId is 193596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.1481G>A	p.Ser494Asn	missense	Exon 10 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.1391G>A	p.Ser464Asn	missense	Exon 9 of 9	NP_001122062.3
	CYP21A2	NM_001368143.2		c.1076G>A	p.Ser359Asn	missense	Exon 10 of 10	NP_001355072.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.1481G>A	p.Ser494Asn	missense	Exon 10 of 10	ENSP00000496625.1
	CYP21A2	ENST00000435122.3	TSL:2	c.1391G>A	p.Ser464Asn	missense	Exon 9 of 9	ENSP00000415043.2
	CYP21A2	ENST00000479074.5	TSL:3	n.1622G>A		non_coding_transcript_exon	Exon 9 of 9

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

GnomAD2 exomes AF: 0.000375 AC: 89 AN: 237558 AF XY: 0.000339

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 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

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

African (AFR) AF: 0.00142 AC: 46 AN: 32398

American (AMR) AF: 0.00271 AC: 116 AN: 42798

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 252 AN: 23780

East Asian (EAS) AF: 0.000721 AC: 28 AN: 38850

South Asian (SAS) AF: 0.00565 AC: 449 AN: 79458

European-Finnish (FIN) AF: 0.00553 AC: 245 AN: 44340

Middle Eastern (MID) AF: 0.00398 AC: 17 AN: 4266

European-Non Finnish (NFE) AF: 0.00262 AC: 2780 AN: 1061160

Other (OTH) AF: 0.00413 AC: 233 AN: 56430

⚠️ 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: 0.00566 AC: 782 AN: 138240 Hom.: 0 Cov.: 33 AF XY: 0.00579 AC XY: 392 AN XY: 67722

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

African (AFR) AF: 0.00190 AC: 75 AN: 39450

American (AMR) AF: 0.00496 AC: 70 AN: 14108

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 21 AN: 2934

East Asian (EAS) AF: 0.00167 AC: 8 AN: 4780

South Asian (SAS) AF: 0.0182 AC: 74 AN: 4058

European-Finnish (FIN) AF: 0.00771 AC: 73 AN: 9464

Middle Eastern (MID) AF: 0.0117 AC: 3 AN: 256

European-Non Finnish (NFE) AF: 0.00697 AC: 422 AN: 60546

Other (OTH) AF: 0.00780 AC: 15 AN: 1922

⚠️ 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: 0.00676 Hom.: 8

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
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
MetaSVM	Benign	-1.0	T
PhyloP100		-0.23
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.076
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.041
MVP		0.25
MPC		0.0098
ClinPred		0.0087	T
GERP RS		2.6
gMVP		0.46
Mutation Taster		=100/0	polymorphism

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