2-178564233-C-T

Position:

chr2-178564233-C-T

Variant summary

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

The NM_001267550.2(TTN):c.81899G>A(p.Arg27300His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 1,613,296 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 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 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 1 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: 0.701

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 -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=0.024486452).

BP6

Variant 2-178564233-C-T is Benign according to our data. Variant chr2-178564233-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47404.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=5, Benign=1}. Variant chr2-178564233-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.81899G>A	p.Arg27300His	missense_variant	326/363	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.81899G>A	p.Arg27300His	missense_variant	326/363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000371

AC:

AN:

247888

Hom.:

AF XY:

0.000439

AC XY:

AN XY:

134476

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.000377

Gnomad NFE exome

AF:

0.000464

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000428

AC:

626

AN:

1461058

Hom.:

Cov.:

AF XY:

0.000450

AC XY:

327

AN XY:

726842

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.000416

Gnomad4 NFE exome

AF:

0.000464

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000348

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000533

Hom.:

Bravo

AF:

0.000499

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000528

AC:

ESP6500EA

AF:

0.000608

AC:

ExAC

AF:

0.000306

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	This variant is associated with the following publications: (PMID: 27930701, 28255936, 17344846) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2022	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TTN: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2023	Variant summary: TTN c.74195G>A (p.Arg24732His) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 247888 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.00037 vs 0.00063), allowing no conclusion about variant significance. c.74195G>A has been reported in the literature in individuals who suffered a sudden unexplained cardiac death (e.g. Campuzano_2015, Campuzano_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 28255936). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2013	Arg24732His in exon 275 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, multiple mammals (guinea pig, hedgehog, elephant, rock hyrax, and platypus) have a histidine (His) at this position, despite high nearby amino acid conserv ation. In addition, computational analyses (biochemical properties, AlignGVGD, a nd PolyPhen2) do not suggest a high likelihood of impact to the protein. This va riant has been identified in 5/8226 European American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs55850344). -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 11, 2021	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2017

- -

Myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 12, 2014

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 16, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.85

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.92

D;D;D;.;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.024

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.57

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

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.069

Sift

Benign

0.77

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

Polyphen

0.0

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

Vest4

0.15

MVP

0.17

MPC

0.10

ClinPred

0.014

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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