2-178741811-G-A

Position:

chr2-178741811-G-A

Variant summary

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

The NM_001267550.2(TTN):c.11422C>T(p.Pro3808Ser) variant causes a missense change. The variant allele was found at a frequency of 0.117 in 1,612,258 control chromosomes in the GnomAD database, including 19,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4958 hom., cov: 32)

Exomes 𝑓: 0.11 ( 14532 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.37

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:

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=0.003395766).

BP6

Variant 2-178741811-G-A is Benign according to our data. Variant chr2-178741811-G-A is described in ClinVar as [Benign]. Clinvar id is 47807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178741811-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.11422C>T	p.Pro3808Ser	missense_variant	48/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.11422C>T	p.Pro3808Ser	missense_variant	48/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.1134-1070G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.204

AC:

31031

AN:

151746

Hom.:

4913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.416

Gnomad AMI

AF:

0.0912

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.0988

Gnomad EAS

AF:

0.211

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0740

Gnomad OTH

AF:

0.170

GnomAD3 exomes

AF:

0.182

AC:

44798

AN:

246178

Hom.:

6770

AF XY:

0.166

AC XY:

22208

AN XY:

133546

show subpopulations

Gnomad AFR exome

AF:

0.423

Gnomad AMR exome

AF:

0.447

Gnomad ASJ exome

AF:

0.104

Gnomad EAS exome

AF:

0.233

Gnomad SAS exome

AF:

0.213

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.0742

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.108

AC:

157457

AN:

1460394

Hom.:

14532

Cov.:

AF XY:

0.108

AC XY:

78307

AN XY:

726436

show subpopulations

Gnomad4 AFR exome

AF:

0.429

Gnomad4 AMR exome

AF:

0.434

Gnomad4 ASJ exome

AF:

0.103

Gnomad4 EAS exome

AF:

0.201

Gnomad4 SAS exome

AF:

0.206

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.0732

Gnomad4 OTH exome

AF:

0.126

GnomAD4 genome

AF:

0.205

AC:

31138

AN:

151864

Hom.:

4958

Cov.:

AF XY:

0.210

AC XY:

15567

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.417

Gnomad4 AMR

AF:

0.314

Gnomad4 ASJ

AF:

0.0988

Gnomad4 EAS

AF:

0.212

Gnomad4 SAS

AF:

0.213

Gnomad4 FIN

AF:

0.109

Gnomad4 NFE

AF:

0.0740

Gnomad4 OTH

AF:

0.167

Alfa

AF:

0.101

Hom.:

2539

Bravo

AF:

0.233

TwinsUK

AF:

0.0725

AC:

269

ALSPAC

AF:

0.0752

AC:

290

ESP6500AA

AF:

0.421

AC:

1541

ESP6500EA

AF:

0.0732

AC:

597

ExAC

AF:

0.174

AC:

21049

Asia WGS

AF:

0.217

AC:

751

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2012	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 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

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2015

This alteration is classified as 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

0.063

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.95

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.50

T;T;.;T;T;T

MetaRNN

Benign

0.0034

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

0.96

P;P;P;P;P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

1.5

N;.;.;N;N;.

REVEL

Benign

0.16

Sift

Benign

0.76

T;.;.;T;T;.

Vest4

0.040

MPC

0.084

ClinPred

0.0058

GERP RS

6.1

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