2-178751146-A-T

Position:

chr2-178751146-A-T

Variant summary

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

The NM_133379.5(TTN):c.11254T>A(p.Ser3752Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,612,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 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 0.00096 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.217

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:):

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=0.0045254827).

BP6

Variant 2-178751146-A-T is Benign according to our data. Variant chr2-178751146-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166277.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr2-178751146-A-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5 linkuse as main transcript	c.11254T>A	p.Ser3752Thr	missense_variant	46/46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 linkuse as main transcript	c.11311+1978T>A		intron_variant		ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 linkuse as main transcript	c.11254T>A	p.Ser3752Thr	missense_variant	46/46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 linkuse as main transcript	c.11311+1978T>A		intron_variant		5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000961

AC:

146

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00340

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000265

AC:

AN:

249070

Hom.:

AF XY:

0.000186

AC XY:

AN XY:

134694

show subpopulations

Gnomad AFR exome

AF:

0.00360

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000863

AC:

126

AN:

1460638

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.00317

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000960

AC:

146

AN:

152078

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00339

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000298

Hom.:

Bravo

AF:

0.00105

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000371

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	Ser3752Thr in exon 45A of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (15/3726) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs144209883). Ser3752Thr in exon 45A of TTN ( rs144209883; allele frequency = 0.4%, 15/3726) ** -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2016	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s). -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TTN: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -

TTN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

5.1

DANN

Benign

0.51

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.28

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.51

REVEL

Benign

0.078

Sift

Benign

0.46

Sift4G

Benign

0.38

Polyphen

0.0060

Vest4

0.24

MVP

0.15

ClinPred

0.014

GERP RS

1.5

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