15-62692931-T-C

Position:

• chr15-62692931-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015059.3(TLN2):​c.1205T>C​(p.Ile402Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLN2 NM_015059.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.94

Genes affected

TLN2 (HGNC:15447): (talin 2) This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments and in spreading and migration of various cell types, including fibroblasts and osteoclasts. This protein has a different pattern of expression compared to talin 1 but, like talin 1, is thought to associate with unique transmembrane receptors to form novel linkages between extracellular matrices and the actin cytoskeleton. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLN2	NM_015059.3	c.1205T>C	p.Ile402Thr	missense_variant	13/59	ENST00000636159.2	NP_055874.2
TLN2	NM_001394547.1	c.1205T>C	p.Ile402Thr	missense_variant	12/58		NP_001381476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLN2	ENST00000636159.2	c.1205T>C	p.Ile402Thr	missense_variant	13/59	5	NM_015059.3	ENSP00000490662	P1
TLN2	ENST00000561311.5	c.1205T>C	p.Ile402Thr	missense_variant	12/58	5		ENSP00000453508	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

May 14, 2024

The c.1205T>C (p.I402T) alteration is located in exon 10 (coding exon 10) of the TLN2 gene. This alteration results from a T to C substitution at nucleotide position 1205, causing the isoleucine (I) at amino acid position 402 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-4.3	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.63	P
Vest4		0.84
MutPred		0.53		Loss of stability (P = 0.005);
MVP		0.51
MPC		0.93
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-62985130;