9-115086012-G-C

Variant names:

• chr9-115086012-G-C
• rs141544394
• NM_002160.4:c.1719C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002160.4(TNC):​c.1719C>G​(p.Cys573Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C573C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNC NM_002160.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 1 publications found

Genes affected

TNC (HGNC:5318): (tenascin C) This gene encodes an extracellular matrix protein with a spatially and temporally restricted tissue distribution. This protein is homohexameric with disulfide-linked subunits, and contains multiple EGF-like and fibronectin type-III domains. It is implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity, and neuronal regeneration. [provided by RefSeq, Jul 2011]

DELEC1 (HGNC:23658): (deleted in esophageal cancer 1) The function of this gene is not known. This gene is located in a region commonly deleted in esophageal squamous cell carcinomas. Gene expression is reduced or absent in these carcinomas and thus this is a candidate tumor suppressor gene for esophageal squamous cell carcinomas. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002160.4. 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
	TNC	NM_002160.4	MANE Select	c.1719C>G	p.Cys573Trp	missense	Exon 3 of 28	NP_002151.2	P24821-1
	TNC	NM_001439065.1		c.1719C>G	p.Cys573Trp	missense	Exon 3 of 30	NP_001425994.1
	TNC	NM_001439066.1		c.1719C>G	p.Cys573Trp	missense	Exon 4 of 31	NP_001425995.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNC	ENST00000350763.9	TSL:1 MANE Select	c.1719C>G	p.Cys573Trp	missense	Exon 3 of 28	ENSP00000265131.4	P24821-1
	TNC	ENST00000423613.6	TSL:1	c.1719C>G	p.Cys573Trp	missense	Exon 3 of 25	ENSP00000411406.2	E9PC84
	TNC	ENST00000542877.6	TSL:1	c.1719C>G	p.Cys573Trp	missense	Exon 3 of 24	ENSP00000442242.1	F5H7V9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250060 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461566 Hom.: 0 Cov.: 55 AF XY: 0.00000138 AC XY: 1 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	8.3
DANN	Benign	0.82
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.74
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.34	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.064	T
MutationAssessor	Pathogenic	4.9	H
PhyloP100		-1.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.88		Loss of disorder (P = 0.0347)
MVP		0.54
MPC		0.78
ClinPred		0.52	D
GERP RS		-8.1
Varity_R		0.90
gMVP		0.98
Mutation Taster		=29/71	disease causing

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: rs141544394; hg19: chr9-117848291;