5-168244493-G-A

Variant names:

• chr5-168244493-G-A
• rs1766374258
• NM_001395460.1:c.5594G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001395460.1(TENM2):​c.5594G>A​(p.Arg1865Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TENM2 NM_001395460.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TENM2	NM_001395460.1	c.5594G>A	p.Arg1865Gln	missense_variant	Exon 28 of 31	ENST00000518659.6	NP_001382389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TENM2	ENST00000518659.6	c.5594G>A	p.Arg1865Gln	missense_variant	Exon 28 of 31	5	NM_001395460.1	ENSP00000429430.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1456356 Hom.: 0 Cov.: 31 AF XY: 0.00000829 AC XY: 6 AN XY: 723976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5567G>A (p.R1856Q) alteration is located in exon 26 (coding exon 26) of the TENM2 gene. This alteration results from a G to A substitution at nucleotide position 5567, causing the arginine (R) at amino acid position 1856 to be replaced by a glutamine (Q). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.076	T;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.039	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.90
MutPred		0.45		Loss of MoRF binding (P = 0.0567);.;.;
MVP		0.66
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.52
gMVP		0.50

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: rs1766374258; hg19: chr5-167671498; COSMIC: COSV69139174; COSMIC: COSV69139174;