Genetic Variant TENM2:p.Ile2186Thr (chr5-168247496-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001395460.1(TENM2):c.6557T>C(p.Ile2186Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TENM2
NM_001395460.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060238153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TENM2	NM_001395460.1 link	c.6557T>C	p.Ile2186Thr	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.6557T>C	p.Ile2186Thr	missense_variant	Exon 29 of 31	5	NM_001395460.1	ENSP00000429430.1		Q9NT68-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248456

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460382

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6530T>C (p.I2177T) alteration is located in exon 27 (coding exon 27) of the TENM2 gene. This alteration results from a T to C substitution at nucleotide position 6530, causing the isoleucine (I) at amino acid position 2177 to be replaced by a threonine (T). 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

0.074

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.23

DEOGEN2

Benign

0.0049

T;T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

-0.090

N;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.23

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.83

T;T;T

Sift4G

Benign

0.69

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.11

MutPred

0.53

Gain of disorder (P = 0.0212);.;.;

MVP

0.043

MPC

0.51

ClinPred

0.18

GERP RS

4.5

Varity_R

0.11

gMVP

0.42

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