chr15-62819540-T-C

Position:

• chr15-62819540-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015059.3(TLN2):​c.6796T>C​(p.Phe2266Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,722 control chromosomes in the GnomAD database, including 24,417 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (2416 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22001 hom.)
• Consequence: TLN2 NM_015059.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.6405873E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLN2	NM_015059.3	c.6796T>C	p.Phe2266Leu	missense_variant	53/59	ENST00000636159.2	NP_055874.2
TLN2	NM_001394547.1	c.6796T>C	p.Phe2266Leu	missense_variant	52/58		NP_001381476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLN2	ENST00000636159.2	c.6796T>C	p.Phe2266Leu	missense_variant	53/59	5	NM_015059.3	ENSP00000490662	P1
TLN2	ENST00000489129.5	n.4711T>C		non_coding_transcript_exon_variant	21/27	1
TLN2	ENST00000561311.5	c.6796T>C	p.Phe2266Leu	missense_variant	52/58	5		ENSP00000453508	P1
TLN2	ENST00000494733.5	c.3538T>C	p.Phe1180Leu	missense_variant	26/32	5		ENSP00000453730

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26622 AN: 152046 Hom.: 2408 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0764

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.162 AC: 40783 AN: 251090 Hom.: 3607 AF XY: 0.165 AC XY: 22380 AN XY: 135710

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.0738

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.171 AC: 249884 AN: 1461558 Hom.: 22001 Cov.: 32 AF XY: 0.172 AC XY: 124736 AN XY: 727096

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.0780

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.175 AC: 26663 AN: 152164 Hom.: 2416 Cov.: 32 AF XY: 0.175 AC XY: 13017 AN XY: 74392

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.0764

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.166

Alfa AF: 0.166 Hom.: 5469

Bravo AF: 0.176

TwinsUK AF: 0.186 AC: 689

ALSPAC AF: 0.181 AC: 699

ESP6500AA AF: 0.193 AC: 851

ESP6500EA AF: 0.171 AC: 1472

ExAC AF: 0.164 AC: 19893

EpiCase AF: 0.164

EpiControl AF: 0.167

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.31	T;T;T
MetaRNN	Benign	0.00086	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.4	N;.;N
Sift	Benign	0.40	T;.;T
Sift4G	Benign	0.36	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.024
MutPred		0.18		Loss of methylation at K2267 (P = 0.0684);.;.;
MPC		0.26
ClinPred		0.018	T
GERP RS		4.6
Varity_R		0.078
gMVP		0.18

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: rs3816988; hg19: chr15-63111739; COSMIC: COSV60888929; COSMIC: COSV60888929;