NM_002160.4:c.6499G>A

Variant names:

• chr9-115021264-C-T
• rs149752009
• NM_002160.4:c.6499G>A

Variant summary

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

The NM_002160.4(TNC):​c.6499G>A​(p.Val2167Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000536 in 1,594,378 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (5 hom.)
• Consequence: TNC NM_002160.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.64
• Publications: 2 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010558158).
• BP6: Variant 9-115021264-C-T is Benign according to our data. Variant chr9-115021264-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 805677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 390 AD gene.

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.6499G>A	p.Val2167Ile	missense	Exon 28 of 28	NP_002151.2	P24821-1
	TNC	NM_001439065.1		c.7048G>A	p.Val2350Ile	missense	Exon 30 of 30	NP_001425994.1
	TNC	NM_001439066.1		c.7048G>A	p.Val2350Ile	missense	Exon 31 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.6499G>A	p.Val2167Ile	missense	Exon 28 of 28	ENSP00000265131.4	P24821-1
	TNC	ENST00000423613.6	TSL:1	c.5680G>A	p.Val1894Ile	missense	Exon 25 of 25	ENSP00000411406.2	E9PC84
	TNC	ENST00000542877.6	TSL:1	c.5410G>A	p.Val1804Ile	missense	Exon 24 of 24	ENSP00000442242.1	F5H7V9

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 392 AN: 142708 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00936

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000979

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000473

Gnomad OTH AF: 0.00104

GnomAD2 exomes AF: 0.000837 AC: 196 AN: 234256 AF XY: 0.000684

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000238

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000743

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000320 AC: 464 AN: 1451556 Hom.: 5 Cov.: 30 AF XY: 0.000304 AC XY: 220 AN XY: 722498

African (AFR) AF: 0.0105 AC: 345 AN: 32814

American (AMR) AF: 0.000530 AC: 23 AN: 43428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25900

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39618

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85248

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52772

Middle Eastern (MID) AF: 0.00184 AC: 10 AN: 5432

European-Non Finnish (NFE) AF: 0.0000289 AC: 32 AN: 1106474

Other (OTH) AF: 0.000802 AC: 48 AN: 59870

GnomAD4 genome AF: 0.00273 AC: 390 AN: 142822 Hom.: 1 Cov.: 32 AF XY: 0.00274 AC XY: 190 AN XY: 69438

African (AFR) AF: 0.00928 AC: 370 AN: 39874

American (AMR) AF: 0.000977 AC: 14 AN: 14328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4592

European-Finnish (FIN) AF: 0.000111 AC: 1 AN: 9046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000473 AC: 3 AN: 63462

Other (OTH) AF: 0.00103 AC: 2 AN: 1944

Alfa AF: 0.000829 Hom.: 3

Bravo AF: 0.00317

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000890 AC: 108

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 56 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.082	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.17	N
PhyloP100		1.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.39	T
Polyphen		0.98	D
Vest4		0.18
MVP		0.81
MPC		0.60
ClinPred		0.031	T
GERP RS		5.1
Varity_R		0.57
gMVP		0.19
Mutation Taster		=86/14	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: rs149752009; hg19: chr9-117783543; COSMIC: COSV106104013;