2-178618381-C-T

Variant names:

• chr2-178618381-C-T
• rs201717871
• NM_001267550.2:c.47077G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.47077G>A​(p.Val15693Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00167 in 1,612,464 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:17
• Conservation: PhyloP100: 4.09

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030773163).
• BP6: Variant 2-178618381-C-T is Benign according to our data. Variant chr2-178618381-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96291.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=3, Uncertain_significance=7}. Variant chr2-178618381-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00177 (2586/1460454) while in subpopulation NFE AF= 0.00222 (2463/1111196). AF 95% confidence interval is 0.00214. There are 3 homozygotes in gnomad4_exome. There are 1274 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.47077G>A	p.Val15693Ile	missense_variant	Exon 252 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.47077G>A	p.Val15693Ile	missense_variant	Exon 252 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000704 AC: 107 AN: 151892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000787 AC: 195 AN: 247668 Hom.: 0 AF XY: 0.000789 AC XY: 106 AN XY: 134356

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000451

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.00177 AC: 2586 AN: 1460454 Hom.: 3 Cov.: 32 AF XY: 0.00175 AC XY: 1274 AN XY: 726526

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000704 AC: 107 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74308

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.000763

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000520 AC: 2

ESP6500EA AF: 0.000485 AC: 4

ExAC AF: 0.000803 AC: 97

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000819

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:9

Apr 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23861362) -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

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

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BP1, BS2 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 16, 2018

Athena Diagnostics

Significance: Likely benign

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

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 14, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TTN c.39373G>A; p.Val13125Ile variant is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. 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.Val13125Ile 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. -

May 26, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

not specified Benign:2

Apr 09, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val13125Ile variant in TTN is classified as likely benign because it has been identified as 0.1% (160/125582) of European chromosomes by gnomAD (http://g nomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Dilated cardiomyopathy 1G Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

TTN-related disorder Benign:1

Oct 12, 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

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Aug 09, 2019

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Apr 08, 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	0.086
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.94
Eigen	Benign	0.056
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;T;D;.;T;T;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.031	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.59	.;.;.;N;.;.;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.72	N;N;.;.;N;N;.
REVEL	Benign	0.093
Sift	Benign	0.28	T;T;.;.;T;T;.
Polyphen		0.21	.;.;.;B;.;.;B
Vest4		0.28
MVP		0.40
MPC		0.077
ClinPred		0.0090	T
GERP RS		5.8

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

LitVar

Other links and lift over

dbSNP: rs201717871; hg19: chr2-179483108; COSMIC: COSV100610560; COSMIC: COSV100610560;