NM_001267550.2:c.34474C>A

Variant names:

Variant summary

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

The NM_001267550.2(TTN):c.34474C>A(p.Pro11492Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,437,438 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 29 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.672

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054418445).

BP6

Variant 2-178675734-G-T is Benign according to our data. Variant chr2-178675734-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 238748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178675734-G-T is described in Lovd as [Benign]. Variant chr2-178675734-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00363 (551/151892) while in subpopulation NFE AF= 0.00494 (335/67866). AF 95% confidence interval is 0.0045. There are 2 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.34474C>A	p.Pro11492Thr	missense_variant	Exon 149 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.34474C>A	p.Pro11492Thr	missense_variant	Exon 149 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

551

AN:

151774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00270

Gnomad ASJ

AF:

0.0312

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00492

Gnomad OTH

AF:

0.00481

GnomAD3 exomes

AF:

0.00449

AC:

324

AN:

72170

Hom.:

AF XY:

0.00443

AC XY:

166

AN XY:

37470

show subpopulations

Gnomad AFR exome

AF:

0.000710

Gnomad AMR exome

AF:

0.00326

Gnomad ASJ exome

AF:

0.0282

Gnomad EAS exome

AF:

0.000132

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00572

Gnomad OTH exome

AF:

0.00563

GnomAD4 exome

AF:

0.00629

AC:

8086

AN:

1285546

Hom.:

Cov.:

AF XY:

0.00615

AC XY:

3847

AN XY:

625506

show subpopulations

Gnomad4 AFR exome

AF:

0.000990

Gnomad4 AMR exome

AF:

0.00286

Gnomad4 ASJ exome

AF:

0.0314

Gnomad4 EAS exome

AF:

0.0000289

Gnomad4 SAS exome

AF:

0.000241

Gnomad4 FIN exome

AF:

0.000207

Gnomad4 NFE exome

AF:

0.00669

Gnomad4 OTH exome

AF:

0.00728

GnomAD4 genome

AF:

0.00363

AC:

551

AN:

151892

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

262

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00269

Gnomad4 ASJ

AF:

0.0312

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00494

Gnomad4 OTH

AF:

0.00476

Alfa

AF:

0.00409

Hom.:

Bravo

AF:

0.00389

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00804

AC:

ExAC

AF:

0.00296

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 27, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: BS2 -

Oct 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TTN-related disorder

Benign:1

Jul 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.70

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0054

Vest4

0.23

MVP

0.74

GERP RS

6.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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