2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAA

Variant names:

• chr2-178713381-T-TACAAA
• rs71393436
• NM_001267550.2:c.26762-14_26762-10dupTTTGT

Variant summary

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

The NM_001267550.2(TTN):​c.26762-14_26762-10dupTTTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,468,510 control chromosomes in the GnomAD database, including 32,223 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4315 hom., cov: 24)
  • Exomes 𝑓: 0.19 (27908 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.08

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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-178713381-T-TACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAA is described in ClinVar as [Likely_benign]. Clinvar id is 46789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.26762-14_26762-10dupTTTGT		intron_variant	Intron 92 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.26762-10_26762-9insTTTGT		intron_variant	Intron 92 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34279 AN: 150788 Hom.: 4305 Cov.: 24

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.194 AC: 19531 AN: 100440 Hom.: 2827 AF XY: 0.189 AC XY: 9657 AN XY: 51018

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.0671

Gnomad EAS exome AF: 0.437

Gnomad SAS exome AF: 0.297

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.191 AC: 251577 AN: 1317606 Hom.: 27908 Cov.: 33 AF XY: 0.193 AC XY: 123636 AN XY: 641652

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.456

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.227 AC: 34318 AN: 150904 Hom.: 4315 Cov.: 24 AF XY: 0.234 AC XY: 17245 AN XY: 73648

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.312

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.222

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jan 13, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.23030-39TTTGT[7] in intron 89 of TTN: This variant is part of a 5-bp repeat ( TTTGT) and adds one repeat unit to the 6 present in the reference sequence. Alt hough this variant is located in the splice region, computational tools do not p redict an effect. This variant is not expected to have clinical significance bec ause similar variants within this repeat region have been identified in 0.4% ( 6 5/15162) of African chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs79799565). Additionally, this variant has been identified in 231 individuals by our laboratory, at least 37 of which were found to have an alternate cause for disease. -

Aug 21, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 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.23030-14_23030-10dupTTTGT 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 0.2 in 131482 control chromosomes in the gnomAD database, including 3533 homozygotes. The observed variant frequency is approximately 315 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

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

- -

Limb-girdle muscular dystrophy, recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Oct 07, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs71393436; hg19: chr2-179578108;