rs185913848

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.53122A>G(p.Lys17708Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000713 in 1,613,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K17708I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

Conservation

PhyloP100: 1.90

Variant links:

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN links:

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02303496).

BP6

Variant 2-178607566-T-C is Benign according to our data. Variant chr2-178607566-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192165.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=2, not_provided=1}. Variant chr2-178607566-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.53122A>G	p.Lys17708Glu	missense_variant	Exon 277 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.53122A>G	p.Lys17708Glu	missense_variant	Exon 277 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000428

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000810

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000399

AC:

AN:

248016

Hom.:

AF XY:

0.000446

AC XY:

AN XY:

134526

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000626

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.000743

AC:

1085

AN:

1461136

Hom.:

Cov.:

AF XY:

0.000726

AC XY:

528

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000902

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

AF:

0.000427

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000810

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000649

Hom.:

Bravo

AF:

0.000514

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00121

AC:

ExAC

AF:

0.000339

AC:

EpiCase

AF:

0.000982

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2Other:1

Sep 27, 2013

GeneDx

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Jan 19, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Apr 09, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

May 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.90

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.82

T;T;T;.;T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.023

T;T;T;T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Pathogenic

4.4

.;.;.;H;.;.;H

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

N;N;.;.;N;N;.

REVEL

Benign

0.21

Sift

Benign

0.18

T;T;.;.;T;T;.

Polyphen

0.11

.;.;.;B;.;.;B

Vest4

0.14

MVP

0.23

MPC

0.13

ClinPred

0.076

GERP RS

6.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over