chr2-178748452-G-A

Variant names:

Variant summary

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

The NM_133379.5(TTN):c.13948C>T(p.Pro4650Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,612,962 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 11 hom. )

Consequence

TTN
NM_133379.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.06

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=0.0030308366).

BP6

Variant 2-178748452-G-A is Benign according to our data. Variant chr2-178748452-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 47765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178748452-G-A is described in Lovd as [Benign]. Variant chr2-178748452-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00233 (354/151998) while in subpopulation NFE AF= 0.0038 (258/67898). AF 95% confidence interval is 0.00342. There are 0 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.13948C>T	p.Pro4650Ser	missense_variant	Exon 46 of 46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11311+4672C>T		intron_variant	Intron 47 of 362	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10 link	c.13948C>T	p.Pro4650Ser	missense_variant	Exon 46 of 46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11311+4672C>T		intron_variant	Intron 47 of 362	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00233

AC:

354

AN:

151880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00178

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000849

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00380

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00198

AC:

493

AN:

248742

Hom.:

AF XY:

0.00195

AC XY:

262

AN XY:

134686

show subpopulations

Gnomad AFR exome

AF:

0.000754

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00350

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00350

AC:

5113

AN:

1460964

Hom.:

Cov.:

AF XY:

0.00339

AC XY:

2461

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.000712

Gnomad4 NFE exome

AF:

0.00431

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00233

AC:

354

AN:

151998

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000747

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000849

Gnomad4 NFE

AF:

0.00380

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00331

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00194

AC:

236

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Apr 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BP4, BS2 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 06, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro4650Ser in exon 45A of TTN: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (209/66040) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs149748934). -

Tibial muscular dystrophy

Benign:1

Aug 01, 2017

Phosphorus, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.44

DANN

Benign

0.34

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.43

M_CAP

Benign

0.0048

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.0

PROVEAN

Benign

0.74

REVEL

Benign

0.017

Sift

Pathogenic

0.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.067

MVP

0.040

ClinPred

0.0035

GERP RS

-4.2

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