Genetic Variant TENM2:p.Val2114Ile (chr5-168247279-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001395460.1(TENM2):c.6340G>A(p.Val2114Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000294 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

TENM2
NM_001395460.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83

Variant links:

Genes affected

TENM2 (HGNC:29943): (teneurin transmembrane protein 2) Enables cell adhesion molecule binding activity and signaling receptor binding activity. Involved in several processes, including calcium-mediated signaling using intracellular calcium source; heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules; and retrograde trans-synaptic signaling by trans-synaptic protein complex. Located in cell-cell junction and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TENM2 links:

TENM2-AS1 (HGNC:56066): (TENM2 antisense RNA 2)

TENM2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08841401).

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TENM2	NM_001395460.1 link	c.6340G>A	p.Val2114Ile	missense_variant	Exon 29 of 31	ENST00000518659.6	NP_001382389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TENM2	ENST00000518659.6 link	c.6340G>A	p.Val2114Ile	missense_variant	Exon 29 of 31	5	NM_001395460.1	ENSP00000429430.1		Q9NT68-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000500

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000148

AC:

AN:

249240

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000298

AC:

435

AN:

1461706

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

214

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000363

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000255

Hom.:

Bravo

AF:

0.000208

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000910

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6313G>A (p.V2105I) alteration is located in exon 27 (coding exon 27) of the TENM2 gene. This alteration results from a G to A substitution at nucleotide position 6313, causing the valine (V) at amino acid position 2105 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.0016

T;T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.088

T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.14

N;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.32

N;N;N

REVEL

Uncertain

0.46

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.16

B;.;D

Vest4

0.26

MVP

0.15

MPC

0.34

ClinPred

0.077

GERP RS

5.4

Varity_R

0.11

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over