2-178630241-G-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):​c.44281C>T​(p.Pro14761Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,612,582 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. P14761P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

7
10
Splicing: ADA: 0.9717
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:18

Conservation

PhyloP100: 7.17

Publications

9 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-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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.044150203).
BP6
Variant 2-178630241-G-A is Benign according to our data. Variant chr2-178630241-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178217.
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000823 (125/151928) while in subpopulation AMR AF = 0.0023 (35/15224). AF 95% confidence interval is 0.0017. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.44281C>T p.Pro14761Ser missense_variant Exon 239 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.44281C>T p.Pro14761Ser missense_variant Exon 239 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000823
AC:
125
AN:
151810
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00230
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:
0.00116
Gnomad OTH
AF:
0.000480
GnomAD2 exomes
AF:
0.000657
AC:
163
AN:
248262
AF XY:
0.000661
show subpopulations
Gnomad AFR exome
AF:
0.000388
Gnomad AMR exome
AF:
0.000697
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00112
Gnomad OTH exome
AF:
0.00116
GnomAD4 exome
AF:
0.00120
AC:
1750
AN:
1460654
Hom.:
4
Cov.:
31
AF XY:
0.00111
AC XY:
808
AN XY:
726580
show subpopulations
African (AFR)
AF:
0.000299
AC:
10
AN:
33420
American (AMR)
AF:
0.000672
AC:
30
AN:
44660
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26104
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39600
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86124
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53388
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.00150
AC:
1668
AN:
1111284
Other (OTH)
AF:
0.000663
AC:
40
AN:
60316
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.462
Heterozygous variant carriers
0
86
172
258
344
430
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
66
132
198
264
330
<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:
0.000823
AC:
125
AN:
151928
Hom.:
0
Cov.:
32
AF XY:
0.000822
AC XY:
61
AN XY:
74216
show subpopulations
African (AFR)
AF:
0.000241
AC:
10
AN:
41470
American (AMR)
AF:
0.00230
AC:
35
AN:
15224
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5156
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4796
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10542
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00116
AC:
79
AN:
67962
Other (OTH)
AF:
0.000475
AC:
1
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
8
15
23
30
38
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000978
Hom.:
9
Bravo
AF:
0.000990
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000612
AC:
5
ExAC
AF:
0.000546
AC:
66
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000873
EpiControl
AF:
0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:18
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:9
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The TTN p.Pro12193Ser variant was not identified in the literature but was identified in dbSNP (ID: rs192766485), LOVD 3.0 and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, EGL Genetics and three other laboratories, as likely benign by Blueprint Genetics and GeneDx and as benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 181 of 279630 chromosomes at a frequency of 0.0006473 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 142 of 127884 chromosomes (freq: 0.00111), Other in 7 of 7120 chromosomes (freq: 0.000983), Latino in 24 of 35264 chromosomes (freq: 0.000681) and African in 8 of 24182 chromosomes (freq: 0.000331), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Pro12193 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Pro12193Ser variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jan 18, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25589632) -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Dec 29, 2018
Athena Diagnostics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jun 01, 2018
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
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

- -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TTN: PM2, BS2 -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Mar 10, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The TTN c.44281C>T; p.Pro14761Ser variant (rs192766485; ClinVar Variation ID: 178217) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has been reported in a cohort of individuals with dilated cardiomyopathy (Roberts 2015). The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Pro14761Ser variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. Roberts AM at al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015 Jan 14;7(270):270ra6. -

not specified Benign:4
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

- -

Nov 09, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Nov 02, 2020
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.36577C>T (p.Pro12193Ser) results in a non-conservative amino acid change located in the I band domain (https://www.cardiodb.org/titin/titin_transcripts.php) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00066 in 248262 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 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 Non-Finnish European origin. c.36577C>T has been reported in the literature in individuals affected with sudden unexplained death/Left Ventricular Non-Compaction (Campuzano_2015). However, this report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=7) or uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

Jun 25, 2015
Blueprint Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dilated cardiomyopathy 1G Uncertain:2
Dec 04, 2015
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hypertrophic cardiomyopathy 9 Uncertain:1
Dec 04, 2015
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Primary dilated cardiomyopathy Uncertain:1
Oct 08, 2014
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiomyopathy Benign:1
May 08, 2020
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Tibial muscular dystrophy Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1
Dec 18, 2019
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
0.29
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
24
DANN
Benign
0.94
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;D;D;.;D;D;D
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.044
T;T;T;T;T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Uncertain
2.5
.;.;.;M;.;.;M
PhyloP100
7.2
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-4.1
D;D;.;.;D;D;.
REVEL
Benign
0.28
Sift
Benign
0.22
T;T;.;.;T;T;.
Polyphen
0.84
.;.;.;P;.;.;P
Vest4
0.51
MVP
0.33
MPC
0.11
ClinPred
0.055
T
GERP RS
6.0
Mutation Taster
=1/99
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Benign
0.65
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs192766485; hg19: chr2-179494968; COSMIC: COSV60108913; COSMIC: COSV60108913; API