2-178739639-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):c.13594A>C(p.Thr4532Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,613,796 control chromosomes in the GnomAD database, including 3,842 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 377 hom., cov: 32)

Exomes 𝑓: 0.053 ( 3465 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.144

Publications

25 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029942393).

BP6

Variant 2-178739639-T-G is Benign according to our data. Variant chr2-178739639-T-G is described in ClinVar as Benign. ClinVar VariationId is 47838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.13594A>C	p.Thr4532Pro	missense	Exon 48 of 363	NP_001254479.2
TTN	NM_001256850.1		c.12643A>C	p.Thr4215Pro	missense	Exon 46 of 313	NP_001243779.1
TTN	NM_133437.4		c.13081A>C	p.Thr4361Pro	missense	Exon 46 of 192	NP_597681.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.13594A>C	p.Thr4532Pro	missense	Exon 48 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.13594A>C	p.Thr4532Pro	missense	Exon 48 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.13318A>C	p.Thr4440Pro	missense	Exon 46 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.0500

AC:

7604

AN:

152104

Hom.:

376

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0116

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.138

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.188

Gnomad SAS

AF:

0.0236

Gnomad FIN

AF:

0.0511

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0464

GnomAD2 exomes

AF:

0.0798

AC:

19804

AN:

248026

AF XY:

0.0703

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.241

Gnomad ASJ exome

AF:

0.0485

Gnomad EAS exome

AF:

0.208

Gnomad FIN exome

AF:

0.0523

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0674

GnomAD4 exome

AF:

0.0530

AC:

77482

AN:

1461574

Hom.:

3465

Cov.:

AF XY:

0.0512

AC XY:

37250

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.00932

AC:

312

AN:

33474

American (AMR)

AF:

0.229

AC:

10235

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0473

AC:

1237

AN:

26126

East Asian (EAS)

AF:

0.189

AC:

7499

AN:

39672

South Asian (SAS)

AF:

0.0201

AC:

1735

AN:

86256

European-Finnish (FIN)

AF:

0.0546

AC:

2913

AN:

53382

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0453

AC:

50335

AN:

1111814

Other (OTH)

AF:

0.0517

AC:

3122

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

4868

9736

14604

19472

24340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2086

4172

6258

8344

10430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0500

AC:

7607

AN:

152222

Hom.:

377

Cov.:

AF XY:

0.0515

AC XY:

3831

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0116

AC:

482

AN:

41542

American (AMR)

AF:

0.138

AC:

2107

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

169

AN:

3470

East Asian (EAS)

AF:

0.188

AC:

975

AN:

5174

South Asian (SAS)

AF:

0.0230

AC:

111

AN:

4830

European-Finnish (FIN)

AF:

0.0511

AC:

542

AN:

10600

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0452

AC:

3077

AN:

68010

Other (OTH)

AF:

0.0450

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

344

687

1031

1374

1718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0498

Hom.:

1272

Bravo

AF:

0.0610

TwinsUK

AF:

0.0483

AC:

179

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.0140

AC:

ESP6500EA

AF:

0.0435

AC:

357

ExAC

AF:

0.0722

AC:

8724

Asia WGS

AF:

0.0770

AC:

265

AN:

3478

EpiCase

AF:

0.0407

EpiControl

AF:

0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 26, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr4294Pro in exon 45B of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 4.5% (300/6614) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/; rs2562829).

Oct 19, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Tibial muscular dystrophy

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Apr 20, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.4

(source)

DANN

Benign

0.62

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.1

PhyloP100

0.14

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.69

REVEL

Benign

0.13

Sift

Benign

0.18

Vest4

0.046

MPC

0.11

ClinPred

0.0021

GERP RS

-3.8

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over