2-178688688-G-A

Position:

chr2-178688688-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_001267550.2(TTN):c.32186C>T(p.Thr10729Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,612,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T10729T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 0.410

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:

LOC124907912 (HGNC:):

LOC124907912 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 Benign. Variant got -8 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=0.005835533).

BP6

Variant 2-178688688-G-A is Benign according to our data. Variant chr2-178688688-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46860.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2, Likely_benign=5}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00111 (169/152284) while in subpopulation AFR AF= 0.00392 (163/41556). AF 95% confidence interval is 0.00343. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TTN	NM_001267550.2 linkuse as main transcript	c.32186C>T	p.Thr10729Met	missense_variant	126/363	ENST00000589042.5
LOC124907912	XR_007087321.1 linkuse as main transcript	n.551G>A		non_coding_transcript_exon_variant	1/2
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2186-25066G>A		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.32186C>T	p.Thr10729Met	missense_variant	126/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.503-45816G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00391

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000241

AC:

AN:

249256

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135236

show subpopulations

Gnomad AFR exome

AF:

0.00355

Gnomad AMR exome

AF:

0.0000869

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:

0.000330

GnomAD4 exome

AF:

0.000113

AC:

165

AN:

1459786

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726332

show subpopulations

Gnomad4 AFR exome

AF:

0.00425

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00000811

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152284

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00392

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000204

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.00398

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000331

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2012	Thr9485Met in exon 123 of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (11/3076) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs115119858). Thr9485Met in exon 123 of TTN ( rs115119858; allele frequency = 0.4%, 11/3076) ** -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2015	- -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 12, 2019

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2013

There is insufficient or conflicting evidence for classification of this alteration. -

TTN-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2020

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). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.5

DANN

Benign

0.79

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.49

T;T;.;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.40

N;.;.;.

REVEL

Benign

0.11

Sift

Benign

0.18

T;.;.;.

Polyphen

0.0

.;.;B;B

Vest4

0.12

MVP

0.12

MPC

0.086

ClinPred

0.0060

GERP RS

-2.4

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