rs200161147

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.32093G>A(p.Arg10698Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,551,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R10698R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Splicing: ADA: 0.0003487

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5O:1

Conservation

PhyloP100: 0.484

Publications

0 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:

LOC124907912 (HGNC:):

LOC124907912 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026729286).

BP6

Variant 2-178689055-C-T is Benign according to our data. Variant chr2-178689055-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202570.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.32093G>A	p.Arg10698Gln	missense_variant	Exon 125 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.32093G>A	p.Arg10698Gln	missense_variant	Exon 125 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes

AF:

0.000358

AC:

AN:

139784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000303

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000688

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000454

Gnomad OTH

AF:

0.000530

GnomAD2 exomes

AF:

0.000239

AC:

AN:

247318

AF XY:

0.000298

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.000403

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000115

AC:

162

AN:

1411222

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

704156

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

32448

American (AMR)

AF:

0.0000452

AC:

AN:

44296

Ashkenazi Jewish (ASJ)

AF:

0.000353

AC:

AN:

25460

East Asian (EAS)

AF:

0.0000772

AC:

AN:

38836

South Asian (SAS)

AF:

0.000743

AC:

AN:

84802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4826

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1069478

Other (OTH)

AF:

0.000137

AC:

AN:

58350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000358

AC:

AN:

139854

Hom.:

Cov.:

AF XY:

0.000314

AC XY:

AN XY:

66912

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

37460

American (AMR)

AF:

0.000302

AC:

AN:

13236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

4724

South Asian (SAS)

AF:

0.000691

AC:

AN:

4342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000454

AC:

AN:

66020

Other (OTH)

AF:

0.000526

AC:

AN:

1902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.000553

Hom.:

Bravo

AF:

0.000374

ESP6500AA

AF:

0.000817

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.000257

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3Other:1

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: BP4 -

Apr 14, 2014

GeneDx

Significance:not provided

Review Status:no classification provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 13, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

May 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Arg9454Gln va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.1% (19/16434) of South Asian chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20016 1147). Arginine (Arg) at position 9454 is not conserved in mammals or evolutiona rily distant species and 1 mammal (weddell seal) carries a glutamine (Gln) at th is position, raising the possibility that this change may be tolerated. In addit ion, this variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicin g. However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg9454Gln variant is unce rtain, it's frequency and the presence of the variant amino acid in another mamm al suggest it is more likely to be benign. -

Mar 22, 2021

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TTN-related disorder

Uncertain:1

Oct 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TTN c.32093G>A variant is predicted to result in the amino acid substitution p.Arg10698Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179553782-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiomyopathy

Uncertain:1

Mar 21, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

.;.;.;.;T

Eigen

Benign

-0.070

Eigen_PC

Benign

0.051

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.57

T;T;.;T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.027

T;T;T;T;T

MetaSVM

Benign

-0.92

PhyloP100

0.48

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

N;.;.;.;N

REVEL

Benign

0.034

Sift

Benign

0.11

T;.;.;.;T

Polyphen

0.20

.;.;B;B;.

Vest4

0.30

MVP

0.16

MPC

0.10

ClinPred

0.013

GERP RS

3.4

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00035

dbscSNV1_RF

Benign

0.026

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