2-178536584-CA-CAA

Position:

chr2-178536584-CA-CAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001267550.2(TTN):c.100172-10_100172-9insT 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 0.0049 in 1,480,024 control chromosomes in the GnomAD database, including 45 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0049 ( 41 hom. )

Consequence

TTN
NM_001267550.2 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:14

Conservation

PhyloP100: 1.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 2-178536584-C-CA is Benign according to our data. Variant chr2-178536584-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47626.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Benign=8}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00457 (693/151632) while in subpopulation SAS AF= 0.00933 (45/4822). AF 95% confidence interval is 0.00717. There are 4 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.100172-10_100172-9insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000589042.5
TTN-AS1	NR_038272.1 linkuse as main transcript	n.316+764dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.100172-10_100172-9insT		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.416+12956dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

693

AN:

151514

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00538

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.00250

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00638

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00550

AC:

817

AN:

148510

Hom.:

AF XY:

0.00623

AC XY:

499

AN XY:

80092

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00449

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0109

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.00643

Gnomad OTH exome

AF:

0.00680

GnomAD4 exome

AF:

0.00494

AC:

6564

AN:

1328392

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

3401

AN XY:

648882

show subpopulations

Gnomad4 AFR exome

AF:

0.000744

Gnomad4 AMR exome

AF:

0.00382

Gnomad4 ASJ exome

AF:

0.0164

Gnomad4 EAS exome

AF:

0.0000530

Gnomad4 SAS exome

AF:

0.0129

Gnomad4 FIN exome

AF:

0.00268

Gnomad4 NFE exome

AF:

0.00453

Gnomad4 OTH exome

AF:

0.00562

GnomAD4 genome

AF:

0.00457

AC:

693

AN:

151632

Hom.:

Cov.:

AF XY:

0.00486

AC XY:

360

AN XY:

74076

show subpopulations

Gnomad4 AFR

AF:

0.00102

Gnomad4 AMR

AF:

0.00538

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00933

Gnomad4 FIN

AF:

0.00250

Gnomad4 NFE

AF:

0.00638

Gnomad4 OTH

AF:

0.00380

Bravo

AF:

0.00412

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2015	92468-10_92468-9insT in intron 305 of TTN: This variant is not expected to have clinical significance because it has been identified in 1.2% (104/8792) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs397517782). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2014	The variant is found in CARDIOMYOPATHY,DCM-CRDM panel(s). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2019	Variant summary: TTN c.92468-10dupT 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 0.0055 in 178860 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 18-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 South Asian origin. Five ClinVar submissions (evaluation after 2014) cite the variant three times as benign, once as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 23, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TTN: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Limb-girdle muscular dystrophy, recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Tibial muscular dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

TTN-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 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

Invitae

Feb 01, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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