rs2066982

Variant names:

• chr6-32058093-C-T
• rs2066982
• NM_001365276.2:c.7790G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32058093-C-T
• chr6-32058093-C-A
• chr6-32058093-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.7790G>A​(p.Arg2597Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,611,260 control chromosomes in the GnomAD database, including 15,087 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2597W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1903 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13184 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.852
• Publications: 14 publications found

Genes affected

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046560466).
• BP6: Variant 6-32058093-C-T is Benign according to our data. Variant chr6-32058093-C-T is described in ClinVar as Benign. ClinVar VariationId is 261164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. 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
	TNXB	NM_001365276.2	MANE Select	c.7790G>A	p.Arg2597Gln	missense	Exon 22 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.8531G>A	p.Arg2844Gln	missense	Exon 23 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.7790G>A	p.Arg2597Gln	missense	Exon 22 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.7790G>A	p.Arg2597Gln	missense	Exon 22 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.8531G>A	p.Arg2844Gln	missense	Exon 23 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.7790G>A	p.Arg2597Gln	missense	Exon 22 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21456 AN: 152050 Hom.: 1898 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.180

GnomAD2 exomes AF: 0.143 AC: 35157 AN: 245316 AF XY: 0.154

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.113 AC: 165180 AN: 1459092 Hom.: 13184 Cov.: 34 AF XY: 0.121 AC XY: 87643 AN XY: 725670

African (AFR) AF: 0.224 AC: 7499 AN: 33444

American (AMR) AF: 0.119 AC: 5304 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2845 AN: 26080

East Asian (EAS) AF: 0.185 AC: 7320 AN: 39654

South Asian (SAS) AF: 0.344 AC: 29604 AN: 86174

European-Finnish (FIN) AF: 0.0685 AC: 3588 AN: 52350

Middle Eastern (MID) AF: 0.265 AC: 1496 AN: 5650

European-Non Finnish (NFE) AF: 0.0899 AC: 99867 AN: 1110836

Other (OTH) AF: 0.127 AC: 7657 AN: 60276

GnomAD4 genome AF: 0.141 AC: 21486 AN: 152168 Hom.: 1903 Cov.: 32 AF XY: 0.145 AC XY: 10801 AN XY: 74416

African (AFR) AF: 0.214 AC: 8891 AN: 41484

American (AMR) AF: 0.150 AC: 2293 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3472

East Asian (EAS) AF: 0.162 AC: 839 AN: 5170

South Asian (SAS) AF: 0.297 AC: 1429 AN: 4816

European-Finnish (FIN) AF: 0.0626 AC: 664 AN: 10614

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.0960 AC: 6528 AN: 68002

Other (OTH) AF: 0.177 AC: 375 AN: 2114

Alfa AF: 0.0988 Hom.: 467

Bravo AF: 0.146

TwinsUK AF: 0.0852 AC: 316

ALSPAC AF: 0.0957 AC: 369

ESP6500AA AF: 0.185 AC: 486

ESP6500EA AF: 0.0880 AC: 453

ExAC AF: 0.149 AC: 17984

Asia WGS AF: 0.270 AC: 941 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.104

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.012
DANN	Benign	0.71
DEOGEN2	Benign	0.017	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.85
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.011
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Vest4		0.0070
ClinPred		0.0037	T
GERP RS		-6.8
Varity_R		0.017
Mutation Taster		=100/0	polymorphism (auto)

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: rs2066982; hg19: chr6-32025870; COSMIC: COSV64489994;