chr2-178713381-T-TACAAAACAAA

Variant names:

• chr2-178713381-T-TACAAAACAAA
• rs71393436
• NM_001267550.2:c.26762-19_26762-10dupTTTGTTTTGT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.26762-19_26762-10dupTTTGTTTTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,468,934 control chromosomes in the GnomAD database, including 71 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (42 hom., cov: 24)
  • Exomes 𝑓: 0.0027 (29 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-TACAAAACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAAACAAA is described in ClinVar as [Likely_benign]. Clinvar id is 167796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0142 (2150/150994) while in subpopulation AFR AF= 0.0452 (1854/41010). AF 95% confidence interval is 0.0435. There are 42 homozygotes in gnomad4. There are 971 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.26762-19_26762-10dupTTTGTTTTGT		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_26762-9insTTTGTTTTGT		intron_variant	Intron 92 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2129 AN: 150878 Hom.: 38 Cov.: 24

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00276

Gnomad SAS AF: 0.00169

Gnomad FIN AF: 0.000763

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.0116

GnomAD3 exomes AF: 0.00456 AC: 458 AN: 100440 Hom.: 5 AF XY: 0.00376 AC XY: 192 AN XY: 51018

Gnomad AFR exome AF: 0.0411

Gnomad AMR exome AF: 0.00459

Gnomad ASJ exome AF: 0.000479

Gnomad EAS exome AF: 0.00231

Gnomad SAS exome AF: 0.000951

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00270 AC: 3562 AN: 1317940 Hom.: 29 Cov.: 33 AF XY: 0.00255 AC XY: 1636 AN XY: 641860

Gnomad4 AFR exome AF: 0.0413

Gnomad4 AMR exome AF: 0.00572

Gnomad4 ASJ exome AF: 0.000283

Gnomad4 EAS exome AF: 0.00216

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.00170

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.0142 AC: 2150 AN: 150994 Hom.: 42 Cov.: 24 AF XY: 0.0132 AC XY: 971 AN XY: 73698

Gnomad4 AFR AF: 0.0452

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00277

Gnomad4 SAS AF: 0.00169

Gnomad4 FIN AF: 0.000763

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.23030-39TTTGT[8] in intron 89 of TTN: This variant is part of a 5 bp repeat (T TTGT) and adds 2 repeat units to 6 present in the reference sequence. It is not expected to have clinical significance because it has been identified in 3.9% (8 2/2118) of African chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs71 393436). Although this variant is located in the splice region, computational to ols do not predict an effect. -

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.23030-19_23030-10dup10 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 0.0069 in 131482 control chromosomes, predominantly at a frequency of 0.043 within the African or African-American subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 69-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 African or African-American origin. Five ClinVar submissions (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

Sep 15, 2015

Eurofins Ntd Llc (ga)

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 03, 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

Jan 23, 2020

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

- -

not provided Benign:1

Aug 26, 2020

GeneDx

Significance: 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

- -

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

- -

Hypertrophic cardiomyopathy 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;