rs16866538

Positions:

Variant summary

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

The NM_001267550.2(TTN):c.982C>T(p.Arg328Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0835 in 1,613,984 control chromosomes in the GnomAD database, including 13,306 homozygotes. In-silico tool predicts 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. R328H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 1792 hom., cov: 32)

Exomes 𝑓: 0.081 ( 11514 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: 5.45

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:

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=2.1404028E-4).

BP6

Variant 2-178795185-G-A is Benign according to our data. Variant chr2-178795185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178795185-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 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.982C>T	p.Arg328Cys	missense_variant	7/363	ENST00000589042.5
TTN	NM_133379.5 linkuse as main transcript	c.982C>T	p.Arg328Cys	missense_variant	7/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.982C>T	p.Arg328Cys	missense_variant	7/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10 linkuse as main transcript	c.982C>T	p.Arg328Cys	missense_variant	7/46	5	NM_133379.5		Q8WZ42-6

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16910

AN:

152028

Hom.:

1794

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.0928

Gnomad ASJ

AF:

0.0617

Gnomad EAS

AF:

0.581

Gnomad SAS

AF:

0.190

Gnomad FIN

AF:

0.0535

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0525

Gnomad OTH

AF:

0.0927

GnomAD3 exomes

AF:

0.124

AC:

31037

AN:

250968

Hom.:

4537

AF XY:

0.122

AC XY:

16554

AN XY:

135624

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.0662

Gnomad EAS exome

AF:

0.597

Gnomad SAS exome

AF:

0.188

Gnomad FIN exome

AF:

0.0489

Gnomad NFE exome

AF:

0.0513

Gnomad OTH exome

AF:

0.0844

GnomAD4 exome

AF:

0.0806

AC:

117804

AN:

1461838

Hom.:

11514

Cov.:

AF XY:

0.0829

AC XY:

60293

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.171

Gnomad4 AMR exome

AF:

0.0997

Gnomad4 ASJ exome

AF:

0.0647

Gnomad4 EAS exome

AF:

0.596

Gnomad4 SAS exome

AF:

0.184

Gnomad4 FIN exome

AF:

0.0462

Gnomad4 NFE exome

AF:

0.0518

Gnomad4 OTH exome

AF:

0.0990

GnomAD4 genome

AF:

0.111

AC:

16923

AN:

152146

Hom.:

1792

Cov.:

AF XY:

0.115

AC XY:

8559

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.167

Gnomad4 AMR

AF:

0.0929

Gnomad4 ASJ

AF:

0.0617

Gnomad4 EAS

AF:

0.580

Gnomad4 SAS

AF:

0.190

Gnomad4 FIN

AF:

0.0535

Gnomad4 NFE

AF:

0.0525

Gnomad4 OTH

AF:

0.0965

Alfa

AF:

0.0731

Hom.:

2308

Bravo

AF:

0.119

TwinsUK

AF:

0.0464

AC:

172

ALSPAC

AF:

0.0514

AC:

198

ESP6500AA

AF:

0.156

AC:

689

ESP6500EA

AF:

0.0531

AC:

457

ExAC

AF:

0.124

AC:

15044

Asia WGS

AF:

0.362

AC:

1259

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2020	- -
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	Eurofins Ntd Llc (ga)	Dec 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2012	Arg328Cys in exon 7 of TTN: This variant is not expected to have clinical signif icance because it has been identified in 15.5% (578/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/rs16866538). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 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. -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Early-onset myopathy with fatal cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2018	- -

Tibial muscular dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

- -

Dilated cardiomyopathy 1G

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2013

This alteration is classified as benign based on a combination of the following: 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Benign

0.68

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.077

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

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

MetaRNN

Benign

0.00021

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

MetaSVM

Benign

-0.89

MutationTaster

Benign

0.00051

P;P;P;P;P;P;P

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.6

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

REVEL

Uncertain

0.42

Sift

Uncertain

0.0070

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.14, 0.77

.;.;.;B;.;.;B;P

Vest4

0.18

MPC

0.12

ClinPred

0.034

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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