chr2-178730390-C-G

Position:

chr2-178730390-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001267550.2(TTN):c.18029-19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,555,784 control chromosomes in the GnomAD database, including 38,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4869 hom., cov: 33)

Exomes 𝑓: 0.20 ( 33602 hom. )

Consequence

TTN
NM_001267550.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.145

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:):

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 (BayesDel_noAF=-0.93).

BP6

Variant 2-178730390-C-G is Benign according to our data. Variant chr2-178730390-C-G is described in ClinVar as [Benign]. Clinvar id is 137838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178730390-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.18029-19G>C		intron_variant		ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.18029-19G>C		intron_variant		5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35153

AN:

151870

Hom.:

4859

Cov.:

show subpopulations

Gnomad AFR

AF:

0.256

Gnomad AMI

AF:

0.502

Gnomad AMR

AF:

0.300

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.652

Gnomad SAS

AF:

0.255

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.224

GnomAD3 exomes

AF:

0.249

AC:

50529

AN:

203110

Hom.:

8143

AF XY:

0.241

AC XY:

26678

AN XY:

110508

show subpopulations

Gnomad AFR exome

AF:

0.257

Gnomad AMR exome

AF:

0.375

Gnomad ASJ exome

AF:

0.168

Gnomad EAS exome

AF:

0.665

Gnomad SAS exome

AF:

0.256

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.229

GnomAD4 exome

AF:

0.200

AC:

281234

AN:

1403796

Hom.:

33602

Cov.:

AF XY:

0.201

AC XY:

138926

AN XY:

692738

show subpopulations

Gnomad4 AFR exome

AF:

0.261

Gnomad4 AMR exome

AF:

0.362

Gnomad4 ASJ exome

AF:

0.164

Gnomad4 EAS exome

AF:

0.661

Gnomad4 SAS exome

AF:

0.245

Gnomad4 FIN exome

AF:

0.146

Gnomad4 NFE exome

AF:

0.177

Gnomad4 OTH exome

AF:

0.215

GnomAD4 genome

AF:

0.232

AC:

35206

AN:

151988

Hom.:

4869

Cov.:

AF XY:

0.234

AC XY:

17395

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.256

Gnomad4 AMR

AF:

0.300

Gnomad4 ASJ

AF:

0.170

Gnomad4 EAS

AF:

0.651

Gnomad4 SAS

AF:

0.255

Gnomad4 FIN

AF:

0.147

Gnomad4 NFE

AF:

0.181

Gnomad4 OTH

AF:

0.227

Alfa

AF:

0.187

Hom.:

568

Bravo

AF:

0.251

Asia WGS

AF:

0.431

AC:

1500

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2012	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Early-onset myopathy with fatal cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

4.1

DANN

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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