chr2-178561780-G-A

Variant names:

• chr2-178561780-G-A
• rs56057221
• NM_001267550.2:c.84352C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.84352C>T​(p.Arg28118Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00342 in 1,613,562 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts 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. R28118L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (91 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (88 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 4.74
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008004248).
• BP6: Variant 2-178561780-G-A is Benign according to our data. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178561780-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.84352C>T	p.Arg28118Cys	missense_variant	Exon 326 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.84352C>T	p.Arg28118Cys	missense_variant	Exon 326 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2740 AN: 152106 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00460 AC: 1140 AN: 248052 AF XY: 0.00321

Gnomad AFR exome AF: 0.0662

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00189 AC: 2762 AN: 1461338 Hom.: 88 Cov.: 32 AF XY: 0.00160 AC XY: 1166 AN XY: 726960

African (AFR) AF: 0.0674 AC: 2257 AN: 33462

American (AMR) AF: 0.00282 AC: 126 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39590

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53374

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.0000657 AC: 73 AN: 1111706

Other (OTH) AF: 0.00441 AC: 266 AN: 60364

GnomAD4 genome AF: 0.0181 AC: 2749 AN: 152224 Hom.: 91 Cov.: 33 AF XY: 0.0171 AC XY: 1271 AN XY: 74416

African (AFR) AF: 0.0633 AC: 2630 AN: 41532

American (AMR) AF: 0.00497 AC: 76 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68014

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00695 Hom.: 55

Bravo AF: 0.0212

ESP6500AA AF: 0.0655 AC: 247

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00550 AC: 665

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:28

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:13

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 14, 2014

GeneDx

Significance: 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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 26, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 12, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:2

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Benign:2

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy Benign:2

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. -

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:2

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Dilated cardiomyopathy 1G Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiomyopathy Benign:1

Mar 08, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 26, 2013

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: 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	0.27
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.88
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D
MetaRNN	Benign	0.0080	T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;.;M
PhyloP100		4.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.8	D;D;.;.;D;D;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;.;.;D;D;.
Polyphen		1.0	.;.;.;D;.;.;D
Vest4		0.44
MVP		0.57
MPC		0.53
ClinPred		0.070	T
GERP RS		5.2
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56057221; hg19: chr2-179426507; COSMIC: COSV99045691; COSMIC: COSV99045691;