2-178531679-C-G

Position:

chr2-178531679-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6

The NM_001267550.2(TTN):c.104936G>C(p.Gly34979Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G34979D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 6.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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=0.21154281).

BP6

Variant 2-178531679-C-G is Benign according to our data. Variant chr2-178531679-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220679.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.104936G>C	p.Gly34979Ala	missense_variant	358/363	ENST00000589042.5
TTN-AS1	NR_038272.1 linkuse as main transcript	n.220-4053C>G		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.104936G>C	p.Gly34979Ala	missense_variant	358/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.416+8043C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000803

AC:

AN:

249104

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

189

AN:

1461684

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000145

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2019	This variant is associated with the following publications: (PMID: 31983221) -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 02, 2019	The p.Gly32411Ala variant in TTN is classified as likely benign because it has b een identified in 0.01% (18/128300) of European chromosomes by gnomAD (http://gn omad.broadinstitute.org) and was identified in trans with a likely pathogenic va riant. ACMG/AMP Criteria applied: BS1_Supporting, BP2. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2023	Variant summary: TTN c.97232G>C (p.Gly32411Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 249104 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8e-05 vs 0.00039), allowing no conclusion about variant significance. c.97232G>C has been reported in the literature in an individual from a Dilated Cardiomyopathy cohort (Mazzarotto_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31983221). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=4) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

TTN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

The TTN c.104936G>C variant is predicted to result in the amino acid substitution p.Gly34979Ala. This variant was reported in a large cohort study of individuals with dilated cardiomyopathy (Reported as chr2:g.179396406 in Supp. Table 3 Mazzarotto et al 2020. PubMed ID: 31983221). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2015

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 12, 2020

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2020

In silico models in agreement (benign);Subpopulation frequency in support of benign classification -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.95

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.86

D;D;D;.;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.21

T;T;T;T;T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Pathogenic

3.3

.;.;.;M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.5

D;D;.;.;D;D;.

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D;.;.;D;D;.

Polyphen

0.60

.;.;.;P;.;.;P

Vest4

0.43

MVP

0.29

MPC

0.15

ClinPred

0.24

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

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