rs72648908

Positions:

chr2-178747646-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_133379.5(TTN):c.14754T>G(p.Pro4918Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,613,284 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 68 hom. )

Consequence

TTN
NM_133379.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.45

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 2-178747646-A-C is Benign according to our data. Variant chr2-178747646-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 47776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178747646-A-C is described in Lovd as [Benign]. Variant chr2-178747646-A-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.45 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00267 (406/152120) while in subpopulation SAS AF= 0.023 (111/4820). AF 95% confidence interval is 0.0196. There are 3 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5 link	c.14754T>G	p.Pro4918Pro	synonymous_variant	46/46	ENST00000360870.10	NP_596870.2	Q8WZ42-6Q7Z3B7
TTN	NM_001267550.2 link	c.11311+5478T>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.14754T>G	p.Pro4918Pro	synonymous_variant	46/46	5	NM_133379.5	ENSP00000354117.4		Q8WZ42-6
TTN	ENST00000589042.5 link	c.11311+5478T>G		intron_variant		5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.00266

AC:

405

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00722

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00309

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00519

AC:

1299

AN:

250242

Hom.:

AF XY:

0.00599

AC XY:

810

AN XY:

135234

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0230

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00318

Gnomad OTH exome

AF:

0.00656

GnomAD4 exome

AF:

0.00498

AC:

7283

AN:

1461164

Hom.:

Cov.:

AF XY:

0.00544

AC XY:

3957

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.000927

Gnomad4 AMR exome

AF:

0.00202

Gnomad4 ASJ exome

AF:

0.00973

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0231

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.00395

Gnomad4 OTH exome

AF:

0.00600

GnomAD4 genome

AF:

0.00267

AC:

406

AN:

152120

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

225

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00722

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0230

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00309

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00366

Hom.:

Bravo

AF:

0.00231

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 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	Jul 24, 2012	Pro4918Pro in Exon 45A of TTN: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.4% (28/7018) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs72648908). -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

TTN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 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_noAF

Benign

-0.31

CADD

Benign

9.7

DANN

Benign

0.77

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