2-178776400-T-G

Position:

chr2-178776400-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.5464A>C(p.Met1822Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,612,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.13

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044240057).

BP6

Variant 2-178776400-T-G is Benign according to our data. Variant chr2-178776400-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203134.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}. Variant chr2-178776400-T-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.5464A>C	p.Met1822Leu	missense_variant	28/363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7
TTN	NM_133379.5 link	c.5464A>C	p.Met1822Leu	missense_variant	28/46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.5464A>C	p.Met1822Leu	missense_variant	28/363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7
TTN	ENST00000360870.10 link	c.5464A>C	p.Met1822Leu	missense_variant	28/46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000280

AC:

AN:

250038

Hom.:

AF XY:

0.000355

AC XY:

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000586

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000257

AC:

375

AN:

1459876

Hom.:

Cov.:

AF XY:

0.000244

AC XY:

177

AN XY:

726358

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000660

Gnomad4 NFE exome

AF:

0.000294

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000184

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000302

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 25, 2022	- -

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, 2025

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.86

Eigen

Benign

-0.16

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.044

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

MetaSVM

Benign

-0.99

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.6

N;N;.;.;N;N;.;N

REVEL

Benign

0.20

Sift

Benign

0.43

T;T;.;.;T;T;.;T

Sift4G

Benign

0.38

.;.;.;.;.;.;.;T

Polyphen

0.031, 0.63

.;.;.;B;.;.;B;P

Vest4

0.39

MutPred

0.26

Loss of loop (P = 0.1258);.;Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);.;.;Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);

MVP

0.49

MPC

0.079

ClinPred

0.029

GERP RS

5.2

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