chr9-115023986-T-C

Position:

• chr9-115023986-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002160.4(TNC):​c.6482A>G​(p.Asn2161Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 1,613,826 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: TNC NM_002160.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.01

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=0.0038039684).
• BP6: Variant 9-115023986-T-C is Benign according to our data. Variant chr9-115023986-T-C is described in ClinVar as [Benign]. Clinvar id is 720440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-115023986-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00559 (851/152344) while in subpopulation AFR AF= 0.0197 (820/41582). AF 95% confidence interval is 0.0186. There are 6 homozygotes in gnomad4. There are 396 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 851 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNC	NM_002160.4	c.6482A>G	p.Asn2161Ser	missense_variant	27/28	ENST00000350763.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNC	ENST00000350763.9	c.6482A>G	p.Asn2161Ser	missense_variant	27/28	1	NM_002160.4	P1
DELEC1	ENST00000649121.1	n.78+54325T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 853 AN: 152226 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00136 AC: 341 AN: 250978 Hom.: 3 AF XY: 0.00103 AC XY: 140 AN XY: 135604

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000478 AC: 698 AN: 1461482 Hom.: 4 Cov.: 31 AF XY: 0.000431 AC XY: 313 AN XY: 726996

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.00559 AC: 851 AN: 152344 Hom.: 6 Cov.: 32 AF XY: 0.00532 AC XY: 396 AN XY: 74496

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000927 Hom.: 2

Bravo AF: 0.00617

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00175 AC: 213

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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	Feb 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

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	0.093
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.17	.;T;.;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.
MetaRNN	Benign	0.0038	T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.33	.;N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	.;N;D;D;N;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	.;D;D;T;T;D
Sift4G	Benign	0.56	T;T;T;T;T;T
Polyphen		0.61	.;P;.;P;.;.
Vest4		0.086
MVP		0.67
MPC		0.28
ClinPred		0.095	T
GERP RS		4.4
Varity_R		0.52
gMVP		0.43

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: rs75198247; hg19: chr9-117786265;