2-178542910-G-A

Variant names:

• chr2-178542910-G-A
• rs56027402
• NM_001267550.2:c.96944C>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.96944C>T​(p.Thr32315Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00341 in 1,612,002 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (90 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (88 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 6.52
• Publications: 4 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=0.0025559068).
• BP6: Variant 2-178542910-G-A is Benign according to our data. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178542910-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 47574.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.96944C>T	p.Thr32315Ile	missense_variant	Exon 348 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.96944C>T	p.Thr32315Ile	missense_variant	Exon 348 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2737 AN: 152060 Hom.: 91 Cov.: 32

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: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00458 AC: 1134 AN: 247478 AF XY: 0.00319

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: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00188 AC: 2747 AN: 1459824 Hom.: 88 Cov.: 32 AF XY: 0.00159 AC XY: 1157 AN XY: 725792

African (AFR) AF: 0.0674 AC: 2255 AN: 33446

American (AMR) AF: 0.00282 AC: 126 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5758

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1110310

Other (OTH) AF: 0.00441 AC: 266 AN: 60324

GnomAD4 genome AF: 0.0180 AC: 2746 AN: 152178 Hom.: 90 Cov.: 32 AF XY: 0.0170 AC XY: 1266 AN XY: 74392

African (AFR) AF: 0.0633 AC: 2627 AN: 41512

American (AMR) AF: 0.00498 AC: 76 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68010

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00638 Hom.: 52

Bravo AF: 0.0212

ESP6500AA AF: 0.0647 AC: 255

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00549 AC: 663

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:12

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. -

Apr 25, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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

- -

-

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

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

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Clinical Genetics, Academic Medical Center

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Early-onset myopathy with fatal cardiomyopathy Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

- -

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

- -

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

- -

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. -

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	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.91
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T;T;.;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;.;L;.;.;L
PhyloP100		6.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.8	D;D;.;.;D;D;.
REVEL	Benign	0.13
Sift	Benign	0.12	T;T;.;.;T;T;.
Polyphen		0.061	.;.;.;B;.;.;B
Vest4		0.54
MVP		0.26
MPC		0.10
ClinPred		0.014	T
GERP RS		5.7
Mutation Taster		=79/21	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: rs56027402; hg19: chr2-179407637; COSMIC: COSV99045689; COSMIC: COSV99045689;