chr2-178784081-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001267550.2(TTN):c.2764C>T(p.Arg922Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,613,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R922H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.01

Publications

6 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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1G
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
early-onset myopathy with fatal cardiomyopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
TTN-related myopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
myopathy, myofibrillar, 9, with early respiratory failure
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
tibial muscular dystrophy
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
autosomal recessive limb-girdle muscular dystrophy type 2J
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
hypertrophic cardiomyopathy 9
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
congenital myopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary skeletal muscle disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

TTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009907901).

BP6

Variant 2-178784081-G-A is Benign according to our data. Variant chr2-178784081-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 202868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00117 (178/152196) while in subpopulation AFR AF = 0.00405 (168/41526). AF 95% confidence interval is 0.00355. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.2764C>T	p.Arg922Cys	missense_variant	Exon 16 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.2764C>T	p.Arg922Cys	missense_variant	Exon 16 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

180

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00144

GnomAD2 exomes

AF:

0.000331

AC:

AN:

250426

AF XY:

0.000266

show subpopulations

Gnomad AFR exome

AF:

0.00461

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

171

AN:

1461048

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

726850

show subpopulations

African (AFR)

AF:

0.00386

AC:

129

AN:

33448

American (AMR)

AF:

0.000268

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5176

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111948

Other (OTH)

AF:

0.000265

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00117

AC:

178

AN:

152196

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00405

AC:

168

AN:

41526

American (AMR)

AF:

0.000392

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000436

Hom.:

Bravo

AF:

0.00117

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Apr 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.2764C>T (p.Arg922Cys) results in a non-conservative amino acid change located in the near Z-disk region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 250426 control chromosomes, predominantly at a frequency of 0.0046 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrences of c.2764C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported in the literature. ClinVar contains an entry for this variant (Variation ID: 202868). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 14, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2017

GeneDx

Significance:Likely 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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg922Cys in exon 16 of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (48/10580) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs72647862). -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: BP4 -

TTN-related disorder

Benign:1

Jun 15, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 08, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

0.17

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.85

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.92

D;D;D;.;D;D;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.0099

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.89

PhyloP100

1.0

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.9

D;D;.;.;D;D;.;D

REVEL

Benign

0.24

Sift

Uncertain

0.0070

D;D;.;.;D;D;.;D

Sift4G

Uncertain

0.043

.;.;.;.;.;.;.;D

Polyphen

0.77, 1.0

.;.;.;P;.;.;P;D

Vest4

0.43

MVP

0.45

MPC

0.14

ClinPred

0.035

GERP RS

3.5

Mutation Taster

=84/16

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over