chr2-178607966-A-G

Variant names:

• chr2-178607966-A-G
• rs2303831
• NM_001267550.2:c.52821T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.52821T>C​(p.Asp17607Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,612,930 control chromosomes in the GnomAD database, including 646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (66 hom., cov: 32)
  • Exomes 𝑓: 0.024 (580 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 1.13
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-178607966-A-G is Benign according to our data. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178607966-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 47065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.52821T>C	p.Asp17607Asp	synonymous_variant	Exon 276 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.52821T>C	p.Asp17607Asp	synonymous_variant	Exon 276 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3277 AN: 151918 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.0951

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0294 AC: 7313 AN: 248414 AF XY: 0.0278

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0240 AC: 35025 AN: 1460894 Hom.: 580 Cov.: 32 AF XY: 0.0236 AC XY: 17122 AN XY: 726744

African (AFR) AF: 0.00416 AC: 139 AN: 33422

American (AMR) AF: 0.0323 AC: 1443 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26114

East Asian (EAS) AF: 0.0923 AC: 3651 AN: 39560

South Asian (SAS) AF: 0.00933 AC: 805 AN: 86238

European-Finnish (FIN) AF: 0.0490 AC: 2617 AN: 53396

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5762

European-Non Finnish (NFE) AF: 0.0220 AC: 24494 AN: 1111388

Other (OTH) AF: 0.0238 AC: 1435 AN: 60324

GnomAD4 genome AF: 0.0215 AC: 3274 AN: 152036 Hom.: 66 Cov.: 32 AF XY: 0.0220 AC XY: 1638 AN XY: 74308

African (AFR) AF: 0.00465 AC: 193 AN: 41536

American (AMR) AF: 0.0233 AC: 356 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

East Asian (EAS) AF: 0.0953 AC: 488 AN: 5120

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4820

European-Finnish (FIN) AF: 0.0450 AC: 477 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1572 AN: 67910

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.0211 Hom.: 52

Bravo AF: 0.0200

Asia WGS AF: 0.0360 AC: 125 AN: 3476

EpiCase AF: 0.0201

EpiControl AF: 0.0219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Apr 29, 2013

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 26, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asp15039Asp in TTN: This variant is not expected to have clinical significance b ecause it does not alter an amino acid residue. It has been identified in 2.2% ( 150/6746) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; rs2303831). Asp15 039Asp in TTN (rs2303831; allele frequency = 2.2%, 150/6746) ** -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

- -

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 -

Jan 11, 2020

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

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

- -

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 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. -

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 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 16, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 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. -

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

- -

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: 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 04, 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
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.1
DANN	Benign	0.76
PhyloP100		1.1
Mutation Taster		=32/68	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: rs2303831; hg19: chr2-179472693; COSMIC: COSV60187895; COSMIC: COSV60187895;