2-178718769-T-G

Variant names:

• chr2-178718769-T-G
• rs16866465
• NM_001267550.2:c.24431A>C

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.24431A>C​(p.Glu8144Ala) variant causes a missense change. The variant allele was found at a frequency of 0.163 in 1,613,646 control chromosomes in the GnomAD database, including 24,242 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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. E8144G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2381 hom., cov: 33)
  • Exomes 𝑓: 0.16 (21861 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 5.95
• Publications: 25 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=0.0055182576).
• BP6: Variant 2-178718769-T-G is Benign according to our data. Variant chr2-178718769-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.24431A>C	p.Glu8144Ala	missense_variant	Exon 84 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.24431A>C	p.Glu8144Ala	missense_variant	Exon 84 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25039 AN: 152014 Hom.: 2378 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.0987

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.165

GnomAD2 exomes AF: 0.177 AC: 44075 AN: 248598 AF XY: 0.179

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.0959

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.163 AC: 238728 AN: 1461514 Hom.: 21861 Cov.: 37 AF XY: 0.165 AC XY: 119738 AN XY: 727042

African (AFR) AF: 0.153 AC: 5134 AN: 33466

American (AMR) AF: 0.175 AC: 7805 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3227 AN: 26132

East Asian (EAS) AF: 0.444 AC: 17621 AN: 39688

South Asian (SAS) AF: 0.220 AC: 18981 AN: 86250

European-Finnish (FIN) AF: 0.0935 AC: 4991 AN: 53390

Middle Eastern (MID) AF: 0.195 AC: 1125 AN: 5766

European-Non Finnish (NFE) AF: 0.153 AC: 169576 AN: 1111742

Other (OTH) AF: 0.170 AC: 10268 AN: 60360

GnomAD4 genome AF: 0.165 AC: 25049 AN: 152132 Hom.: 2381 Cov.: 33 AF XY: 0.166 AC XY: 12333 AN XY: 74384

African (AFR) AF: 0.153 AC: 6363 AN: 41514

American (AMR) AF: 0.170 AC: 2596 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3472

East Asian (EAS) AF: 0.432 AC: 2228 AN: 5152

South Asian (SAS) AF: 0.223 AC: 1076 AN: 4818

European-Finnish (FIN) AF: 0.0987 AC: 1047 AN: 10610

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10474 AN: 67978

Other (OTH) AF: 0.170 AC: 359 AN: 2114

Alfa AF: 0.160 Hom.: 9018

Bravo AF: 0.172

TwinsUK AF: 0.149 AC: 551

ALSPAC AF: 0.154 AC: 592

ESP6500AA AF: 0.149 AC: 590

ESP6500EA AF: 0.152 AC: 1266

ExAC AF: 0.176 AC: 21301

Asia WGS AF: 0.330 AC: 1151 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 16, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2012

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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Apr 03, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu6900Ala in exon 81 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 14% (1033/6756) of European American chromosomes and 15% (470/3284) of African American chromosomes from a broad popu lation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs16866465) -

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

Jan 12, 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 12, 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

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 21, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy Benign:2

Jan 12, 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 12, 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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1G Benign:1

Jan 12, 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

Jan 16, 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	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.75
Eigen	Benign	-0.12
Eigen_PC	Benign	0.038
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T;T;.;T
MetaRNN	Benign	0.0055	T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		6.0
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.4	N;.;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.023	D;.;.;.
Polyphen		0.0030	.;.;B;B
Vest4		0.078
MPC		0.092
ClinPred		0.018	T
GERP RS		6.0
Mutation Taster		=63/37	polymorphism

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: rs16866465; hg19: chr2-179583496; COSMIC: COSV59921595; COSMIC: COSV59921595;