rs6446

Variant names:

• chr6-32041119-G-A
• rs6446
• NM_000500.9:c.1473G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000500.9(CYP21A2):​c.1473G>A​(p.Pro491Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 146,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (232 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP21A2 NM_000500.9 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.316
• Publications: 5 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-32041119-G-A is Benign according to our data. Variant chr6-32041119-G-A is described in ClinVar as Benign. ClinVar VariationId is 256288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.316 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.1473G>A	p.Pro491Pro	synonymous_variant	Exon 10 of 10	ENST00000644719.2	NP_000491.4
TNXB	NM_001365276.2	c.*230C>T		downstream_gene_variant		ENST00000644971.2	NP_001352205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.1473G>A	p.Pro491Pro	synonymous_variant	Exon 10 of 10		NM_000500.9	ENSP00000496625.1
TNXB	ENST00000644971.2	c.*230C>T		downstream_gene_variant			NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.000772 AC: 113 AN: 146280 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000888

Gnomad AMI AF: 0.00124

Gnomad AMR AF: 0.00130

Gnomad ASJ AF: 0.00129

Gnomad EAS AF: 0.000818

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000597

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000628

Gnomad OTH AF: 0.000497

GnomAD2 exomes AF: 0.0000335 AC: 8 AN: 238752 AF XY: 0.0000230

Gnomad AFR exome AF: 0.000202

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.000340

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000426 AC: 612 AN: 1436166 Hom.: 232 Cov.: 33 AF XY: 0.000460 AC XY: 329 AN XY: 714624

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

African (AFR) AF: 0.000606 AC: 20 AN: 32988

American (AMR) AF: 0.000939 AC: 41 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.00428 AC: 106 AN: 24752

East Asian (EAS) AF: 0.000587 AC: 23 AN: 39202

South Asian (SAS) AF: 0.000433 AC: 37 AN: 85406

European-Finnish (FIN) AF: 0.00119 AC: 55 AN: 46388

Middle Eastern (MID) AF: 0.000227 AC: 1 AN: 4414

European-Non Finnish (NFE) AF: 0.000264 AC: 290 AN: 1100130

Other (OTH) AF: 0.000659 AC: 39 AN: 59204

⚠️ 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: 0.000772 AC: 113 AN: 146406 Hom.: 0 Cov.: 33 AF XY: 0.000879 AC XY: 63 AN XY: 71640

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

African (AFR) AF: 0.000886 AC: 36 AN: 40652

American (AMR) AF: 0.00130 AC: 19 AN: 14646

Ashkenazi Jewish (ASJ) AF: 0.00129 AC: 4 AN: 3090

East Asian (EAS) AF: 0.000820 AC: 4 AN: 4876

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4694

European-Finnish (FIN) AF: 0.000597 AC: 6 AN: 10052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000628 AC: 41 AN: 65282

Other (OTH) AF: 0.000492 AC: 1 AN: 2034

⚠️ 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: 0.00214 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.9
DANN	Benign	0.59
PhyloP100		0.32
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: rs6446; hg19: chr6-32008896;