5-167952704-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001395460.1(TENM2):c.829A>G(p.Asn277Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,028 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TENM2 NM_001395460.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TENM2
• BP4: Computational evidence support a benign effect (MetaRNN=0.18848845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM2	NM_001395460.1	c.829A>G	p.Asn277Asp	missense_variant	6/31	ENST00000518659.6
LOC105377709	XR_941186.3	n.224+688T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM2	ENST00000518659.6	c.829A>G	p.Asn277Asp	missense_variant	6/31	5	NM_001395460.1	P1
	ENST00000523050.1	n.78+688T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459028 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725414

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.829A>G (p.N277D) alteration is located in exon 4 (coding exon 4) of the TENM2 gene. This alteration results from a A to G substitution at nucleotide position 829, causing the asparagine (N) at amino acid position 277 to be replaced by an aspartic acid (D). 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	0.23
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.0040	T;T;T
Eigen	Benign	0.044
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.86	D;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.67	T;T;T
Polyphen		0.57	P;P;B
Vest4		0.49
MutPred		0.52		Loss of MoRF binding (P = 0.0442);.;.;
MVP		0.068
MPC		0.85
ClinPred		0.63	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.24

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: rs1436837143; hg19: chr5-167379709;