chr15-62650084-C-T

Position:

• chr15-62650084-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015059.3(TLN2):​c.137C>T​(p.Ala46Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLN2 NM_015059.3 missense, splice_region
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

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]

TLN2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLN2	NM_015059.3	c.137C>T	p.Ala46Val	missense_variant, splice_region_variant	5/59	ENST00000636159.2	NP_055874.2
TLN2	NM_001394547.1	c.137C>T	p.Ala46Val	missense_variant, splice_region_variant	4/58		NP_001381476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLN2	ENST00000636159.2	c.137C>T	p.Ala46Val	missense_variant, splice_region_variant	5/59	5	NM_015059.3	ENSP00000490662.2
TLN2	ENST00000561311.5	c.137C>T	p.Ala46Val	missense_variant, splice_region_variant	4/58	5		ENSP00000453508.1
TLN2	ENST00000474847.2	n.86C>T		non_coding_transcript_exon_variant	1/5	5

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

Sep 24, 2024

The c.137C>T (p.A46V) alteration is located in exon 2 (coding exon 2) of the TLN2 gene. This alteration results from a C to T substitution at nucleotide position 137, causing the alanine (A) at amino acid position 46 to be replaced by a valine (V). 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	0.17
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
Sift	Benign	0.094	T
Sift4G	Benign	0.13	T
Polyphen		0.86	P
Vest4		0.45
MutPred		0.35		Loss of disorder (P = 0.0656);
MVP		0.57
MPC		0.26
ClinPred		0.71	D
GERP RS		6.0
Varity_R		0.34
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.040		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: chr15-62942283;