2-178702075-TAA-TAAA

Position:

• chr2-178702075-TAA-TAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.30512-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0536 in 1,473,500 control chromosomes in the GnomAD database, including 2,713 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1111 hom., cov: 31)
  • Exomes 𝑓: 0.049 (1602 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.83

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-178702075-T-TA is Benign according to our data. Variant chr2-178702075-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 46838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.30512-10dupT		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.30512-10dupT		intron_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0918 AC: 13753 AN: 149800 Hom.: 1097 Cov.: 31

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0322

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0722

GnomAD3 exomes AF: 0.107 AC: 18502 AN: 172130 Hom.: 628 AF XY: 0.105 AC XY: 9716 AN XY: 92726

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.0430

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.0724

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0868

GnomAD4 exome AF: 0.0492 AC: 65135 AN: 1323594 Hom.: 1602 Cov.: 32 AF XY: 0.0513 AC XY: 33752 AN XY: 657808

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.0383

Gnomad4 EAS exome AF: 0.0292

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.0626

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0594

GnomAD4 genome AF: 0.0922 AC: 13815 AN: 149906 Hom.: 1111 Cov.: 31 AF XY: 0.0975 AC XY: 7140 AN XY: 73196

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.0322

Gnomad4 EAS AF: 0.0340

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.0603

Gnomad4 NFE AF: 0.0270

Gnomad4 OTH AF: 0.0719

Bravo AF: 0.0987

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: TTN c.26780-10dupT alters a non-conserved 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 0.1 in 201596 control chromosomes in the gnomAD database, including 809 homozygotes. The observed variant frequency is approximately 166 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.26780-10dupT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x) /likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Early-onset myopathy with fatal cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Tibial muscular dystrophy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Limb-girdle muscular dystrophy, recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517532; hg19: chr2-179566802;