chr2-178713381-TACAAA-T

Variant names:

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

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.26762-14_26762-10delTTTGT variant causes a intron change. The variant allele was found at a frequency of 0.00124 in 1,468,982 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 24)
  • Exomes 𝑓: 0.00091 (6 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 3.61

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-TACAAA-T is Benign according to our data. Variant chr2-178713381-TACAAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 46788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178713381-TACAAA-T is described in Lovd as [Benign]. Variant chr2-178713381-TACAAA-T is described in Lovd as [Benign]. Variant chr2-178713381-TACAAA-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00412 (622/151012) while in subpopulation AFR AF= 0.0128 (524/41026). AF 95% confidence interval is 0.0119. There are 3 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.26762-14_26762-10delTTTGT		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.26762-14_26762-10delTTTGT		intron_variant	Intron 92 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 612 AN: 150896 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00238

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000395

Gnomad SAS AF: 0.000422

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.00385

GnomAD3 exomes AF: 0.00152 AC: 153 AN: 100440 Hom.: 1 AF XY: 0.00131 AC XY: 67 AN XY: 51018

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.000486

Gnomad SAS exome AF: 0.000317

Gnomad FIN exome AF: 0.000148

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000356

GnomAD4 exome AF: 0.000914 AC: 1204 AN: 1317970 Hom.: 6 AF XY: 0.000882 AC XY: 566 AN XY: 641862

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00680

Gnomad4 EAS exome AF: 0.000233

Gnomad4 SAS exome AF: 0.000480

Gnomad4 FIN exome AF: 0.000384

Gnomad4 NFE exome AF: 0.000433

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00412 AC: 622 AN: 151012 Hom.: 3 Cov.: 24 AF XY: 0.00399 AC XY: 294 AN XY: 73706

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.00238

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000396

Gnomad4 SAS AF: 0.000422

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.000339

Gnomad4 OTH AF: 0.00381

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

-

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

- -

Jan 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BS1 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3 Other:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

23030-14_23030-10del variant in intron 89 of TTN: This variant is not expected to have clinical significance as it is part of a 5 bp repeat (TTTGT) and removes one repeat unit to 6 present in the reference sequence. 23030-14_23030-10delTTTGT in intron 89 of TTN (allele frequency = n/a) -

May 21, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 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_23030-10delTTTGT 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 0.0015 in 100440 control chromosomes, predominantly at a frequency of 0.013 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 21-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 a benign polymorphism found primarily in populations of African or African-American origin. Two ClinVar submitters (evaluation after 2014) cite the variant as benign and likely benign. Based on the evidence outlined above, the variant was classified as benign. -

TTN-related disorder Benign:1

May 29, 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 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Dec 09, 2020

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

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;