6-32041574-C-T

Variant names:

• chr6-32041574-C-T
• rs6457475
• NM_000500.9:c.*440C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000500.9(CYP21A2):​c.*440C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,050,532 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (28 hom., cov: 24)
  • Exomes 𝑓: 0.0081 (79 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.56
• Publications: 6 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-32041574-C-T is Benign according to our data. Variant chr6-32041574-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1191218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

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.*440C>T		3_prime_UTR	Exon 10 of 10	NP_000491.4
	TNXB	NM_001365276.2	MANE Select	c.12634-124G>A		intron	N/A	NP_001352205.1	P22105-3
	CYP21A2	NM_001128590.4		c.*440C>T		3_prime_UTR	Exon 9 of 9	NP_001122062.3	P08686-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.*440C>T		3_prime_UTR	Exon 10 of 10	ENSP00000496625.1	P08686-1
	TNXB	ENST00000644971.2	MANE Select	c.12634-124G>A		intron	N/A	ENSP00000496448.1	P22105-3
	TNXB	ENST00000451343.4	TSL:1	c.1921-124G>A		intron	N/A	ENSP00000407685.1	P22105-2

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2772 AN: 146860 Hom.: 28 Cov.: 24

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0904

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00178

Gnomad FIN AF: 0.000955

Gnomad MID AF: 0.0226

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0374

GnomAD4 exome AF: 0.00814 AC: 7357 AN: 903548 Hom.: 79 Cov.: 13 AF XY: 0.00786 AC XY: 3638 AN XY: 462990

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

African (AFR) AF: 0.0195 AC: 401 AN: 20560

American (AMR) AF: 0.0218 AC: 755 AN: 34658

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 1207 AN: 21128

East Asian (EAS) AF: 0.000951 AC: 32 AN: 33650

South Asian (SAS) AF: 0.00115 AC: 78 AN: 68112

European-Finnish (FIN) AF: 0.00137 AC: 65 AN: 47602

Middle Eastern (MID) AF: 0.0158 AC: 60 AN: 3790

European-Non Finnish (NFE) AF: 0.00645 AC: 4080 AN: 632826

Other (OTH) AF: 0.0165 AC: 679 AN: 41222

⚠️ 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: 0.0189 AC: 2775 AN: 146984 Hom.: 28 Cov.: 24 AF XY: 0.0173 AC XY: 1244 AN XY: 71752

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

African (AFR) AF: 0.0235 AC: 903 AN: 38416

American (AMR) AF: 0.0381 AC: 571 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 304 AN: 3362

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5136

South Asian (SAS) AF: 0.00178 AC: 8 AN: 4500

European-Finnish (FIN) AF: 0.000955 AC: 10 AN: 10466

Middle Eastern (MID) AF: 0.0276 AC: 8 AN: 290

European-Non Finnish (NFE) AF: 0.0133 AC: 889 AN: 66910

Other (OTH) AF: 0.0370 AC: 75 AN: 2028

⚠️ 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: 0.0166 Hom.: 9

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.041
DANN	Benign	0.60
PhyloP100		-5.6
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: rs6457475; hg19: chr6-32009351; COSMIC: COSV64489863; COSMIC: COSV64489863;