chr2-178756224-C-T

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.11252G>A(p.Gly3751Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.9 in 1,594,874 control chromosomes in the GnomAD database, including 650,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3751E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.87 ( 58115 hom., cov: 33)

Exomes 𝑓: 0.90 ( 592684 hom. )

Consequence

TTN
NM_001267550.2 missense, splice_region

Scores

Splicing: ADA: 0.002052

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.78

Publications

34 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=8.103962E-7).

BP6

Variant 2-178756224-C-T is Benign according to our data. Variant chr2-178756224-C-T is described in ClinVar as [Benign]. Clinvar id is 47852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.11252G>A	p.Gly3751Asp	missense_variant, splice_region_variant	Exon 46 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7
TTN	NM_133379.5 link	c.10303+2760G>A		intron_variant	Intron 44 of 45	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.11252G>A	p.Gly3751Asp	missense_variant, splice_region_variant	Exon 46 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7
TTN	ENST00000360870.10 link	c.10303+2760G>A		intron_variant	Intron 44 of 45	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6

Frequencies

GnomAD3 genomes

AF:

0.870

AC:

132390

AN:

152096

Hom.:

58094

Cov.:

show subpopulations

Gnomad AFR

AF:

0.835

Gnomad AMI

AF:

0.952

Gnomad AMR

AF:

0.719

Gnomad ASJ

AF:

0.918

Gnomad EAS

AF:

0.781

Gnomad SAS

AF:

0.791

Gnomad FIN

AF:

0.890

Gnomad MID

AF:

0.949

Gnomad NFE

AF:

0.931

Gnomad OTH

AF:

0.895

GnomAD2 exomes

AF:

0.838

AC:

203686

AN:

242962

AF XY:

0.850

show subpopulations

Gnomad AFR exome

AF:

0.839

Gnomad AMR exome

AF:

0.570

Gnomad ASJ exome

AF:

0.913

Gnomad EAS exome

AF:

0.755

Gnomad FIN exome

AF:

0.891

Gnomad NFE exome

AF:

0.930

Gnomad OTH exome

AF:

0.869

GnomAD4 exome

AF:

0.903

AC:

1303069

AN:

1442660

Hom.:

592684

Cov.:

AF XY:

0.902

AC XY:

644760

AN XY:

714838

show subpopulations

African (AFR)

AF:

0.833

AC:

27515

AN:

33034

American (AMR)

AF:

0.585

AC:

25739

AN:

44034

Ashkenazi Jewish (ASJ)

AF:

0.917

AC:

23445

AN:

25568

East Asian (EAS)

AF:

0.783

AC:

30835

AN:

39368

South Asian (SAS)

AF:

0.796

AC:

67445

AN:

84726

European-Finnish (FIN)

AF:

0.888

AC:

46283

AN:

52120

Middle Eastern (MID)

AF:

0.929

AC:

5283

AN:

5688

European-Non Finnish (NFE)

AF:

0.931

AC:

1023189

AN:

1098588

Other (OTH)

AF:

0.896

AC:

53335

AN:

59534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

5472

10943

16415

21886

27358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21406

42812

64218

85624

107030

<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:

0.870

AC:

132452

AN:

152214

Hom.:

58115

Cov.:

AF XY:

0.865

AC XY:

64327

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.834

AC:

34652

AN:

41528

American (AMR)

AF:

0.718

AC:

10974

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.918

AC:

3189

AN:

3472

East Asian (EAS)

AF:

0.781

AC:

4039

AN:

5174

South Asian (SAS)

AF:

0.791

AC:

3810

AN:

4816

European-Finnish (FIN)

AF:

0.890

AC:

9448

AN:

10612

Middle Eastern (MID)

AF:

0.949

AC:

279

AN:

294

European-Non Finnish (NFE)

AF:

0.931

AC:

63300

AN:

68022

Other (OTH)

AF:

0.897

AC:

1895

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

860

1720

2579

3439

4299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.909

Hom.:

281364

Bravo

AF:

0.854

TwinsUK

AF:

0.931

AC:

3453

ALSPAC

AF:

0.930

AC:

3584

ESP6500AA

AF:

0.840

AC:

3266

ESP6500EA

AF:

0.932

AC:

7723

ExAC

AF:

0.849

AC:

102606

Asia WGS

AF:

0.795

AC:

2768

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Jan 31, 2013

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. -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 18, 2018

Athena Diagnostics

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.91

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.43

T;T

MetaRNN

Benign

8.1e-7

T;T

MetaSVM

Benign

-1.0

PhyloP100

3.8

PROVEAN

Benign

-0.84

.;N

REVEL

Benign

0.037

Sift

Benign

1.0

.;T

Vest4

0.14

MPC

0.11

ClinPred

0.014

GERP RS

4.2

Mutation Taster

=45/55

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0021

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over