rs183950862

Positions:

chr2-178646559-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_001267550.2(TTN):c.40223A>G(p.Glu13408Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000227 in 1,540,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense, splice_region

Scores

Splicing: ADA: 0.02789

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 3.71

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 -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.

BP4

Computational evidence support a benign effect (MetaRNN=0.015589327).

BP6

Variant 2-178646559-T-C is Benign according to our data. Variant chr2-178646559-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220885.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00122 (185/152186) while in subpopulation AFR AF= 0.00428 (178/41552). AF 95% confidence interval is 0.00377. There are 0 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.40223A>G	p.Glu13408Gly	missense_variant, splice_region_variant	216/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2185+2058T>C		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.40223A>G	p.Glu13408Gly	missense_variant, splice_region_variant	216/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.502+48878T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

183

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000196

AC:

AN:

147834

Hom.:

AF XY:

0.000138

AC XY:

AN XY:

79646

show subpopulations

Gnomad AFR exome

AF:

0.00342

Gnomad AMR exome

AF:

0.000207

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000446

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

165

AN:

1388694

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

685298

show subpopulations

Gnomad4 AFR exome

AF:

0.00408

Gnomad4 AMR exome

AF:

0.000169

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000382

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000373

Gnomad4 OTH exome

AF:

0.000417

GnomAD4 genome

AF:

0.00122

AC:

185

AN:

152186

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00428

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TTN: BP4, BS1 -
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	Jun 02, 2020	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2023	Variant summary: TTN c.32594-529A>G is located at a position not widely known to affect splicing. 4/4 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 0.0002 in 147834 control chromosomes, predominantly at a frequency of 0.0034 within the African or African-American subpopulation in the gnomAD database. c.32594-529A>G has been reported in the literature in an individuals affected with cerebral palsy and authors classified the variant as uncertain significance (example: Pingel_2018). This report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

TTN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2020

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.31

T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-0.76

MutationTaster

Benign

0.98

D;D;D;D;D;D

PROVEAN

Uncertain

-4.0

.;D

REVEL

Benign

0.21

Sift

Pathogenic

0.0

.;D

Vest4

0.27

MVP

0.84

MPC

0.23

ClinPred

0.14

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.028

dbscSNV1_RF

Benign

0.28

SpliceAI score (max)

0.0

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