chr2-178663651-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.36508G>A(p.Glu12170Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 1,612,440 control chromosomes in the GnomAD database, including 16,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E12170V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.20 ( 5345 hom., cov: 31)

Exomes 𝑓: 0.088 ( 10783 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.198

Publications

12 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:

LOC124906100 (HGNC:):

LOC124906100 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=2.773106E-4).

BP6

Variant 2-178663651-C-T is Benign according to our data. Variant chr2-178663651-C-T is described in ClinVar as Benign. ClinVar VariationId is 192215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.36508G>A	p.Glu12170Lys	missense_variant	Exon 171 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.36508G>A	p.Glu12170Lys	missense_variant	Exon 171 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

30145

AN:

150750

Hom.:

5306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.463

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.0715

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.0584

Gnomad OTH

AF:

0.164

GnomAD2 exomes

AF:

0.146

AC:

36104

AN:

247358

AF XY:

0.139

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.253

Gnomad ASJ exome

AF:

0.0694

Gnomad EAS exome

AF:

0.134

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.0595

Gnomad OTH exome

AF:

0.115

GnomAD4 exome

AF:

0.0883

AC:

129052

AN:

1461572

Hom.:

10783

Cov.:

AF XY:

0.0903

AC XY:

65681

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.480

AC:

16067

AN:

33470

American (AMR)

AF:

0.251

AC:

11217

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0701

AC:

1831

AN:

26128

East Asian (EAS)

AF:

0.107

AC:

4254

AN:

39692

South Asian (SAS)

AF:

0.231

AC:

19888

AN:

86254

European-Finnish (FIN)

AF:

0.122

AC:

6516

AN:

53402

Middle Eastern (MID)

AF:

0.0947

AC:

546

AN:

5764

European-Non Finnish (NFE)

AF:

0.0558

AC:

62049

AN:

1111792

Other (OTH)

AF:

0.111

AC:

6684

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

6991

13982

20972

27963

34954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2810

5620

8430

11240

14050

<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:

0.201

AC:

30251

AN:

150868

Hom.:

5345

Cov.:

AF XY:

0.205

AC XY:

15121

AN XY:

73786

show subpopulations

African (AFR)

AF:

0.464

AC:

19099

AN:

41172

American (AMR)

AF:

0.228

AC:

3452

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.0715

AC:

247

AN:

3456

East Asian (EAS)

AF:

0.130

AC:

654

AN:

5034

South Asian (SAS)

AF:

0.239

AC:

1134

AN:

4746

European-Finnish (FIN)

AF:

0.121

AC:

1272

AN:

10508

Middle Eastern (MID)

AF:

0.113

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0584

AC:

3941

AN:

67518

Other (OTH)

AF:

0.166

AC:

348

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

979

1958

2937

3916

4895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.120

Hom.:

1196

Bravo

AF:

0.216

TwinsUK

AF:

0.0561

AC:

208

ALSPAC

AF:

0.0553

AC:

213

ESP6500AA

AF:

0.473

AC:

829

ESP6500EA

AF:

0.0560

AC:

223

ExAC

AF:

0.146

AC:

17622

EpiCase

AF:

0.0554

EpiControl

AF:

0.0585

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 15, 2018

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. -

Nov 02, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.7

(source)

DANN

Benign

0.72

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.0062

LIST_S2

Benign

0.11

MetaRNN

Benign

0.00028

MetaSVM

Benign

-0.93

PhyloP100

0.20

Vest4

0.066

ClinPred

0.0036

GERP RS

3.8

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over