chr2-178562809-T-C

Variant names:

• chr2-178562809-T-C
• rs3829746
• NM_001267550.2:c.83323A>G

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.83323A>G​(p.Ile27775Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,612,474 control chromosomes in the GnomAD database, including 74,712 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 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. I27775T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.36 (11855 hom., cov: 33)
  • Exomes 𝑓: 0.27 (62857 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 0.477
• Publications: 46 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=4.253756E-6).
• BP6: Variant 2-178562809-T-C is Benign according to our data. Variant chr2-178562809-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.83323A>G	p.Ile27775Val	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.83323A>G	p.Ile27775Val	missense_variant	Exon 326 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54920 AN: 151850 Hom.: 11806 Cov.: 33

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.352 AC: 86795 AN: 246406 AF XY: 0.349

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.269 AC: 392178 AN: 1460506 Hom.: 62857 Cov.: 40 AF XY: 0.274 AC XY: 198713 AN XY: 726470

African (AFR) AF: 0.556 AC: 18602 AN: 33458

American (AMR) AF: 0.425 AC: 18935 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7303 AN: 26116

East Asian (EAS) AF: 0.694 AC: 27427 AN: 39530

South Asian (SAS) AF: 0.504 AC: 43445 AN: 86222

European-Finnish (FIN) AF: 0.277 AC: 14763 AN: 53294

Middle Eastern (MID) AF: 0.307 AC: 1771 AN: 5768

European-Non Finnish (NFE) AF: 0.217 AC: 241659 AN: 1111286

Other (OTH) AF: 0.303 AC: 18273 AN: 60288

GnomAD4 genome AF: 0.362 AC: 55030 AN: 151968 Hom.: 11855 Cov.: 33 AF XY: 0.372 AC XY: 27638 AN XY: 74304

African (AFR) AF: 0.542 AC: 22461 AN: 41434

American (AMR) AF: 0.384 AC: 5864 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 986 AN: 3468

East Asian (EAS) AF: 0.701 AC: 3595 AN: 5132

South Asian (SAS) AF: 0.514 AC: 2479 AN: 4822

European-Finnish (FIN) AF: 0.285 AC: 3022 AN: 10586

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15318 AN: 67952

Other (OTH) AF: 0.336 AC: 711 AN: 2116

Alfa AF: 0.280 Hom.: 23953

Bravo AF: 0.376

TwinsUK AF: 0.214 AC: 792

ALSPAC AF: 0.216 AC: 834

ESP6500AA AF: 0.532 AC: 2013

ESP6500EA AF: 0.223 AC: 1841

ExAC AF: 0.350 AC: 42293

Asia WGS AF: 0.618 AC: 2146 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:11

Sep 27, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Aug 18, 2020

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

Significance: Likely 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. -

Jul 23, 2013

Eurofins Ntd Llc (ga)

Significance: 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

- -

-

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

BA1 -

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

- -

not provided Benign:2

Nov 02, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

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 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 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

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	0.054
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.9
DANN	Benign	0.86
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.59	T;T;T;.;T;T;T
MetaRNN	Benign	0.0000043	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.54	.;.;.;N;.;.;N
PhyloP100		0.48
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.40	N;N;.;.;N;N;.
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;.;.;T;T;.
Polyphen		0.0	.;.;.;B;.;.;B
Vest4		0.048
MPC		0.070
ClinPred		0.0010	T
GERP RS		5.2
Mutation Taster		=100/0	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: rs3829746; hg19: chr2-179427536; COSMIC: COSV60156917; COSMIC: COSV60156917;