2-178713381-TACAAAACAAAACAAA-TACAAAACAAA

Position:

chr2-178713381-TACAAAACAAAACAAA-TACAAAACAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001267550.2(TTN):c.26762-14_26762-10del variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 3.61

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-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/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.26762-14_26762-10del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2186-346_2186-342del		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.26762-14_26762-10del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.503-21096_503-21092del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00406

AC:

612

AN:

150896

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00131

AC XY:

AN XY:

51018

show subpopulations

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.:

AF XY:

0.000882

AC XY:

566

AN XY:

641862

show subpopulations

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.:

Cov.:

AF XY:

0.00399

AC XY:

294

AN XY:

73706

show subpopulations

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:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TTN: BS1, BS2 -

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 19, 2013	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) -

TTN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 09, 2020

- -

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