2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAA

Position:

chr2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001267550.2(TTN):c.26762-10_26762-9insTTTGT variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.08

Variant links:

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 links:

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]

TTN-AS1 links:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.26762-10_26762-9insTTTGT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2186-346_2186-342dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.26762-10_26762-9insTTTGT		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.503-21096_503-21092dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34279

AN:

150788

Hom.:

4305

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.193

AC XY:

123636

AN XY:

641652

show subpopulations

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.:

AF XY:

0.234

AC XY:

17245

AN XY:

73648

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2014	The variant is found in CARDIOMYOPATHY panel(s). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 11, 2023

- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 07, 2016

- -

Early-onset myopathy with fatal cardiomyopathy

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

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Tibial muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over