rs2274750

chr9-115040992-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002160.4(TNC):c.5341G>A(p.Ala1781Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,613,834 control chromosomes in the GnomAD database, including 1,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (338 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1556 hom.)
• Consequence: TNC NM_002160.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.52

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016574562).
• BP6: Variant 9-115040992-C-T is Benign according to our data. Variant chr9-115040992-C-T is described in ClinVar as [Benign]. Clinvar id is 586835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-115040992-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNC	NM_002160.4	c.5341G>A	p.Ala1781Thr	missense_variant	19/28	ENST00000350763.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNC	ENST00000350763.9	c.5341G>A	p.Ala1781Thr	missense_variant	19/28	1	NM_002160.4	P1
DELEC1	ENST00000649121.1	n.79-43263C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8487 AN: 151950 Hom.: 339 Cov.: 32

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0947

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0586

GnomAD3 exomes AF: 0.0554 AC: 13933 AN: 251304 Hom.: 642 AF XY: 0.0493 AC XY: 6699 AN XY: 135842

Gnomad AFR exome AF: 0.0834

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.0256

Gnomad EAS exome AF: 0.100

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.0777

Gnomad NFE exome AF: 0.0292

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0372 AC: 54402 AN: 1461766 Hom.: 1556 Cov.: 34 AF XY: 0.0362 AC XY: 26351 AN XY: 727190

Gnomad4 AFR exome AF: 0.0872

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.0959

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0761

Gnomad4 NFE exome AF: 0.0291

Gnomad4 OTH exome AF: 0.0447

GnomAD4 genome AF: 0.0559 AC: 8506 AN: 152068 Hom.: 338 Cov.: 32 AF XY: 0.0572 AC XY: 4256 AN XY: 74356

Gnomad4 AFR AF: 0.0807

Gnomad4 AMR AF: 0.0951

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0759

Gnomad4 NFE AF: 0.0294

Gnomad4 OTH AF: 0.0613

Alfa AF: 0.0360 Hom.: 303

Bravo AF: 0.0601

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0272 AC: 105

ESP6500AA AF: 0.0908 AC: 400

ESP6500EA AF: 0.0309 AC: 266

ExAC AF: 0.0515 AC: 6255

Asia WGS AF: 0.0680 AC: 237 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	This variant is associated with the following publications: (PMID: 16741161) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -

Autosomal dominant nonsyndromic hearing loss 56 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;.
MetaRNN	Benign	0.0017	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.42	T
REVEL	Benign	0.29
Sift4G	Benign	0.066	T;D;T;T;T;T
Polyphen		0.95, 0.99	.;P;.;D;.;.
Vest4		0.30
MPC		0.49
ClinPred		0.030	T
GERP RS		4.1
Varity_R		0.19
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs2274750; hg19: chr9-117803271; COSMIC: COSV60782497;