rs140909116

Positions:

chr2-178748464-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_133379.5(TTN):c.13936A>G(p.Lys4646Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00676 in 1,613,048 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 71 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.106

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027041435).

BP6

Variant 2-178748464-T-C is Benign according to our data. Variant chr2-178748464-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 47764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178748464-T-C is described in Lovd as [Benign]. Variant chr2-178748464-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00581 (884/152096) while in subpopulation SAS AF= 0.00932 (45/4826). AF 95% confidence interval is 0.00716. There are 8 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.13936A>G	p.Lys4646Glu	missense_variant	46/46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11311+4660A>G		intron_variant		ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 link	c.13936A>G	p.Lys4646Glu	missense_variant	46/46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11311+4660A>G		intron_variant		5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00582

AC:

885

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00453

Gnomad ASJ

AF:

0.0427

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00754

Gnomad OTH

AF:

0.00957

GnomAD3 exomes

AF:

0.00801

AC:

1990

AN:

248470

Hom.:

AF XY:

0.00886

AC XY:

1192

AN XY:

134594

show subpopulations

Gnomad AFR exome

AF:

0.000947

Gnomad AMR exome

AF:

0.00421

Gnomad ASJ exome

AF:

0.0407

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0114

Gnomad FIN exome

AF:

0.00291

Gnomad NFE exome

AF:

0.00841

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.00686

AC:

10028

AN:

1460952

Hom.:

Cov.:

AF XY:

0.00715

AC XY:

5200

AN XY:

726786

show subpopulations

Gnomad4 AFR exome

AF:

0.00126

Gnomad4 AMR exome

AF:

0.00504

Gnomad4 ASJ exome

AF:

0.0405

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0119

Gnomad4 FIN exome

AF:

0.00324

Gnomad4 NFE exome

AF:

0.00616

Gnomad4 OTH exome

AF:

0.00935

GnomAD4 genome

AF:

0.00581

AC:

884

AN:

152096

Hom.:

Cov.:

AF XY:

0.00554

AC XY:

412

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00452

Gnomad4 ASJ

AF:

0.0427

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00932

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.00752

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.00831

Hom.:

Bravo

AF:

0.00556

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00931

AC:

ExAC

AF:

0.00818

AC:

993

Asia WGS

AF:

0.00549

AC:

AN:

3476

EpiCase

AF:

0.0103

EpiControl

AF:

0.0110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2014	p.Lys4646Glu in exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 1.1% (182/16562) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs140909116). -

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TTN: BP4, BS1, BS2 -

TTN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.12

DANN

Benign

0.55

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

PROVEAN

Benign

-1.2

REVEL

Benign

0.041

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.021

Polyphen

0.0020

Vest4

0.14

MVP

0.30

ClinPred

0.0085

GERP RS

-2.5

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