rs12994774

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_001267550.2(TTN):c.36655T>G(p.Leu12219Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.18 ( 2431 hom., cov: 23)

Exomes 𝑓: 0.11 ( 34361 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.21

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:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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=0.0017544031).

BP6

Variant 2-178663311-A-C is Benign according to our data. Variant chr2-178663311-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220982.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr2-178663311-A-C is described in Lovd as [Likely_benign]. Variant chr2-178663311-A-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.36655T>G	p.Leu12219Val	missense_variant	173/363	ENST00000589042.5
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2185+18810A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.36655T>G	p.Leu12219Val	missense_variant	173/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.502+65630A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

20356

AN:

115166

Hom.:

2428

Cov.:

FAILED QC

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.426

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.448

Gnomad SAS

AF:

0.309

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.208

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.171

GnomAD3 exomes

AF:

0.0997

AC:

21960

AN:

220158

Hom.:

5322

AF XY:

0.0944

AC XY:

11239

AN XY:

119108

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.166

Gnomad ASJ exome

AF:

0.0592

Gnomad EAS exome

AF:

0.333

Gnomad SAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0503

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.105

AC:

137173

AN:

1302676

Hom.:

34361

Cov.:

AF XY:

0.111

AC XY:

71844

AN XY:

647128

show subpopulations

Gnomad4 AFR exome

AF:

0.177

Gnomad4 AMR exome

AF:

0.191

Gnomad4 ASJ exome

AF:

0.156

Gnomad4 EAS exome

AF:

0.494

Gnomad4 SAS exome

AF:

0.289

Gnomad4 FIN exome

AF:

0.127

Gnomad4 NFE exome

AF:

0.0697

Gnomad4 OTH exome

AF:

0.144

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.177

AC:

20375

AN:

115242

Hom.:

2431

Cov.:

AF XY:

0.176

AC XY:

9706

AN XY:

55072

show subpopulations

Gnomad4 AFR

AF:

0.210

Gnomad4 AMR

AF:

0.223

Gnomad4 ASJ

AF:

0.184

Gnomad4 EAS

AF:

0.448

Gnomad4 SAS

AF:

0.308

Gnomad4 FIN

AF:

0.141

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.175

Alfa

AF:

0.186

Hom.:

814

ExAC

AF:

0.0689

AC:

8020

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant has not been reported. Only affects this transcript. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.012

DANN

Benign

0.63

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.068

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

P;P;P;P;P;P

Vest4

0.026

MPC

0.084

ClinPred

0.00046

GERP RS

-4.3

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