chr2-178770209-C-T

Variant names:

• chr2-178770209-C-T
• rs2306636
• NM_001267550.2:c.8492G>A

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.8492G>A​(p.Ser2831Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,614,076 control chromosomes in the GnomAD database, including 4,018 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (389 hom., cov: 32)
  • Exomes 𝑓: 0.055 (3629 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 3.00
• 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=0.0010921359).
• BP6: Variant 2-178770209-C-T is Benign according to our data. Variant chr2-178770209-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.8492G>A	p.Ser2831Asn	missense_variant	Exon 36 of 363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.8492G>A	p.Ser2831Asn	missense_variant	Exon 36 of 46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.8492G>A	p.Ser2831Asn	missense_variant	Exon 36 of 363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.8492G>A	p.Ser2831Asn	missense_variant	Exon 36 of 46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.0517 AC: 7860 AN: 152110 Hom.: 387 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0560

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0829 AC: 20816 AN: 251236 AF XY: 0.0746

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.0568

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.0525

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0699

GnomAD4 exome AF: 0.0550 AC: 80440 AN: 1461848 Hom.: 3629 Cov.: 33 AF XY: 0.0539 AC XY: 39165 AN XY: 727232

African (AFR) AF: 0.00989 AC: 331 AN: 33480

American (AMR) AF: 0.228 AC: 10215 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1442 AN: 26136

East Asian (EAS) AF: 0.194 AC: 7681 AN: 39686

South Asian (SAS) AF: 0.0415 AC: 3578 AN: 86258

European-Finnish (FIN) AF: 0.0546 AC: 2918 AN: 53420

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5768

European-Non Finnish (NFE) AF: 0.0457 AC: 50869 AN: 1111982

Other (OTH) AF: 0.0545 AC: 3292 AN: 60396

GnomAD4 genome AF: 0.0517 AC: 7866 AN: 152228 Hom.: 389 Cov.: 32 AF XY: 0.0537 AC XY: 3993 AN XY: 74412

African (AFR) AF: 0.0118 AC: 492 AN: 41562

American (AMR) AF: 0.140 AC: 2141 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0560 AC: 194 AN: 3466

East Asian (EAS) AF: 0.185 AC: 955 AN: 5158

South Asian (SAS) AF: 0.0465 AC: 224 AN: 4820

European-Finnish (FIN) AF: 0.0512 AC: 543 AN: 10598

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0466 AC: 3169 AN: 68008

Other (OTH) AF: 0.0468 AC: 99 AN: 2114

Alfa AF: 0.0527 Hom.: 1408

Bravo AF: 0.0618

TwinsUK AF: 0.0477 AC: 177

ALSPAC AF: 0.0506 AC: 195

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0451 AC: 388

ExAC AF: 0.0759 AC: 9220

Asia WGS AF: 0.0870 AC: 300 AN: 3476

EpiCase AF: 0.0427

EpiControl AF: 0.0453

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

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

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser2831Asn in exon 36 of TTN: This variant is not expected to have clinical sign ificance because it has been identified in 4.8% (332/7020) of European American chromosomes and 1.4% (52/3738) of African American chromosomes from a broad popu lation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs2306636) -

Oct 19, 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. -

Sep 06, 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

- -

-

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

- -

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. -

Tibial muscular dystrophy 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. -

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype Benign:1

Aug 23, 2012

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	0.044
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.94
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.33	T;T;T;.;T;T;T;T
MetaRNN	Benign	0.0011	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		3.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	2.5	N;N;.;.;N;N;.;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;.;.;T;T;.;T
Sift4G	Benign	1.0	.;.;.;.;.;.;.;T
Polyphen		0.0	.;.;.;B;.;.;B;B
Vest4		0.016
MPC		0.078
ClinPred		0.011	T
GERP RS		6.1
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2306636; hg19: chr2-179634936; COSMIC: COSV59946607; COSMIC: COSV59946607;