chr2-178581678-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001267550.2(TTN):c.66590G>A(p.Arg22197Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000639 in 1,612,470 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22197W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 1 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 3.92

Publications

4 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14143303).

BP6

Variant 2-178581678-C-T is Benign according to our data. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886. Variant chr2-178581678-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 165886.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.66590G>A	p.Arg22197Gln	missense_variant	Exon 316 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.66590G>A	p.Arg22197Gln	missense_variant	Exon 316 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000776

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.0000971

AC:

AN:

247274

AF XY:

0.0000745

show subpopulations

Gnomad AFR exome

AF:

0.000389

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000737

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1460340

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

726420

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.000634

AC:

AN:

39430

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

1111208

Other (OTH)

AF:

0.000249

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000158

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000778

AC:

AN:

5144

South Asian (SAS)

AF:

0.000208

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67970

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.000164

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000253

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Dec 09, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 07, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Apr 03, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg19629Gln variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 1/3960 A frican American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS/). Computational analyses (biochemical amino acid properties , conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support fo r or against an impact to the protein. Additional information is needed to fully assess the clinical significance of this variant. -

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

- -

Cardiovascular phenotype

Uncertain:1

Nov 20, 2015

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R13132Q variant (also known as c.39395G>A), located in coding exon 143 of the TTN gene, results from a G to A substitution at nucleotide position 39395. The arginine at codon 13132 is replaced by glutamine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs374656017. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12236) total alleles studied, having been observed in 0.03% (1/3960) African American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.016

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.28

.;.;.;N;.;.;N

PhyloP100

3.9

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.7

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

REVEL

Benign

0.21

Sift

Benign

0.23

T;T;.;.;T;T;.

Polyphen

1.0

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

Vest4

0.49

MVP

0.25

MPC

0.46

ClinPred

0.078

GERP RS

4.5

Mutation Taster

=92/8

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