chr2-178536584-C-CA

Variant names:

• chr2-178536584-C-CA
• rs397517782
• NM_001267550.2:c.100172-10dupT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001267550.2(TTN):​c.100172-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,480,024 control chromosomes in the GnomAD database, including 45 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (41 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:14
• Conservation: PhyloP100: 1.72

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

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 2-178536584-C-CA is Benign according to our data. Variant chr2-178536584-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47626.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=6}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00457 (693/151632) while in subpopulation SAS AF= 0.00933 (45/4822). AF 95% confidence interval is 0.00717. There are 4 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.100172-10dupT		intron_variant	Intron 356 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.100172-10_100172-9insT		intron_variant	Intron 356 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 693 AN: 151514 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00538

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.00250

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00550 AC: 817 AN: 148510 Hom.: 9 AF XY: 0.00623 AC XY: 499 AN XY: 80092

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00643

Gnomad OTH exome AF: 0.00680

GnomAD4 exome AF: 0.00494 AC: 6564 AN: 1328392 Hom.: 41 Cov.: 31 AF XY: 0.00524 AC XY: 3401 AN XY: 648882

Gnomad4 AFR exome AF: 0.000744

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000530

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.00453

Gnomad4 OTH exome AF: 0.00562

GnomAD4 genome AF: 0.00457 AC: 693 AN: 151632 Hom.: 4 Cov.: 33 AF XY: 0.00486 AC XY: 360 AN XY: 74076

Gnomad4 AFR AF: 0.00102

Gnomad4 AMR AF: 0.00538

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00933

Gnomad4 FIN AF: 0.00250

Gnomad4 NFE AF: 0.00638

Gnomad4 OTH AF: 0.00380

Bravo AF: 0.00412

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Aug 13, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.92468-10dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0055 in 178860 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 18-folds over the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Five ClinVar submissions (evaluation after 2014) cite the variant three times as benign, once as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 16, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in CARDIOMYOPATHY,DCM-CRDM panel(s). -

Nov 13, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

92468-10_92468-9insT in intron 305 of TTN: This variant is not expected to have clinical significance because it has been identified in 1.2% (104/8792) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs397517782). -

Jan 26, 2024

Athena Diagnostics

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

- -

not provided Benign:4

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BS1, BS2 -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy, recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TTN-related disorder Benign:1

Jul 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

- -

Cardiomyopathy Benign:1

Apr 25, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517782; hg19: chr2-179401311;