rs200017524

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.58612A>G(p.Thr19538Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000262 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. T19538K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.91

Publications

2 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009403706).

BP6

Variant 2-178593688-T-C is Benign according to our data. Variant chr2-178593688-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178205.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 = 0.00141 (215/152188) while in subpopulation AFR AF = 0.00465 (193/41546). AF 95% confidence interval is 0.00411. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.58612A>G	p.Thr19538Ala	missense_variant	Exon 298 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.58612A>G	p.Thr19538Ala	missense_variant	Exon 298 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00463

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.000359

AC:

AN:

248186

AF XY:

0.000230

show subpopulations

Gnomad AFR exome

AF:

0.00472

Gnomad AMR exome

AF:

0.000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1461184

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.00475

AC:

159

AN:

33460

American (AMR)

AF:

0.000336

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111620

Other (OTH)

AF:

0.000265

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.00141

AC:

215

AN:

152188

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00465

AC:

193

AN:

41546

American (AMR)

AF:

0.000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67986

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000681

Hom.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.00379

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000439

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 31, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr16970Ala in exon 247 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.5% (45/9792) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200017524). -

Jun 12, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.50908A>G (p.Thr16970Ala) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 248186 control chromosomes, predominantly at a frequency of 0.0047 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. To our knowledge, no occurrence of c.50908A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Jan 11, 2018

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. -

Sep 08, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

TTN-related disorder

Benign:1

Nov 10, 2020

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

Feb 02, 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

- -

not provided

Benign:1

Jul 20, 2018

Athena Diagnostics

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

- -

Cardiovascular phenotype

Benign:1

Jul 09, 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

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.85

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.018

MetaRNN

Benign

0.0094

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

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.6

.;.;.;L;.;.;L

PhyloP100

4.9

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.3

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

REVEL

Benign

0.25

Sift

Benign

0.10

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

Polyphen

0.90

.;.;.;P;.;.;P

Vest4

0.37

MVP

0.27

MPC

0.33

ClinPred

0.025

GERP RS

6.0

Mutation Taster

=66/34

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