2-178630241-G-A

Variant names:

• chr2-178630241-G-A
• rs192766485
• NM_001267550.2:c.44281C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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: Splicing: ADA: 0.9717
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:18
• Conservation: PhyloP100: 7.17
• Publications: 9 publications found

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]

ACMG classification

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 CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 178217. Variant chr2-178630241-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id 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
TTN	NM_001267550.2	c.44281C>T	p.Pro14761Ser	missense_variant	Exon 239 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.44281C>T	p.Pro14761Ser	missense_variant	Exon 239 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000823 AC: 125 AN: 151810 Hom.: 0 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.000823 AC: 125 AN: 151928 Hom.: 0 Cov.: 32 AF XY: 0.000822 AC XY: 61 AN XY: 74216

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

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:9 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:9

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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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) -

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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

Other links and lift over

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