rs2163008

Positions:

chr2-178663651-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):c.36508G>A(p.Glu12170Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 1,612,440 control chromosomes in the GnomAD database, including 16,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E12170V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.20 ( 5345 hom., cov: 31)

Exomes 𝑓: 0.088 ( 10783 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.198

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 (HGNC:):

TTN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.

BP4

Computational evidence support a benign effect (MetaRNN=2.773106E-4).

BP6

Variant 2-178663651-C-T is Benign according to our data. Variant chr2-178663651-C-T is described in ClinVar as [Benign]. Clinvar id is 192215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178663651-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.36508G>A	p.Glu12170Lys	missense_variant	171/363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.36508G>A	p.Glu12170Lys	missense_variant	171/363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

30145

AN:

150750

Hom.:

5306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.463

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.0715

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.0584

Gnomad OTH

AF:

0.164

GnomAD3 exomes

AF:

0.146

AC:

36104

AN:

247358

Hom.:

4279

AF XY:

0.139

AC XY:

18717

AN XY:

134618

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.253

Gnomad ASJ exome

AF:

0.0694

Gnomad EAS exome

AF:

0.134

Gnomad SAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.0595

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.0883

AC:

129052

AN:

1461572

Hom.:

10783

Cov.:

AF XY:

0.0903

AC XY:

65681

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.480

Gnomad4 AMR exome

AF:

0.251

Gnomad4 ASJ exome

AF:

0.0701

Gnomad4 EAS exome

AF:

0.107

Gnomad4 SAS exome

AF:

0.231

Gnomad4 FIN exome

AF:

0.122

Gnomad4 NFE exome

AF:

0.0558

Gnomad4 OTH exome

AF:

0.111

GnomAD4 genome

AF:

0.201

AC:

30251

AN:

150868

Hom.:

5345

Cov.:

AF XY:

0.205

AC XY:

15121

AN XY:

73786

show subpopulations

Gnomad4 AFR

AF:

0.464

Gnomad4 AMR

AF:

0.228

Gnomad4 ASJ

AF:

0.0715

Gnomad4 EAS

AF:

0.130

Gnomad4 SAS

AF:

0.239

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.0584

Gnomad4 OTH

AF:

0.166

Alfa

AF:

0.116

Hom.:

1108

Bravo

AF:

0.216

TwinsUK

AF:

0.0561

AC:

208

ALSPAC

AF:

0.0553

AC:

213

ESP6500AA

AF:

0.473

AC:

829

ESP6500EA

AF:

0.0560

AC:

223

ExAC

AF:

0.146

AC:

17622

EpiCase

AF:

0.0554

EpiControl

AF:

0.0585

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2018	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.7

DANN

Benign

0.72

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.0062

LIST_S2

Benign

0.11

MetaRNN

Benign

0.00028

MetaSVM

Benign

-0.93

Vest4

0.066

ClinPred

0.0036

GERP RS

3.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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