2-178652927-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001267550.2(TTN):c.38880A>G(p.Pro12960=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,606,042 control chromosomes in the GnomAD database, including 735 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P12960P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 71 hom., cov: 31)

Exomes 𝑓: 0.026 ( 664 hom. )

Consequence

TTN
NM_001267550.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -3.81

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 2-178652927-T-C is Benign according to our data. Variant chr2-178652927-T-C is described in ClinVar as [Benign]. Clinvar id is 413166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178652927-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.81 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.38880A>G	p.Pro12960=	synonymous_variant	200/363	ENST00000589042.5
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2185+8426T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.38880A>G	p.Pro12960=	synonymous_variant	200/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.502+55246T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3523

AN:

151700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00497

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.0940

Gnomad SAS

AF:

0.0312

Gnomad FIN

AF:

0.0450

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.0247

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0327

AC:

7832

AN:

239346

Hom.:

198

AF XY:

0.0320

AC XY:

4174

AN XY:

130336

show subpopulations

Gnomad AFR exome

AF:

0.00487

Gnomad AMR exome

AF:

0.0343

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.101

Gnomad SAS exome

AF:

0.0282

Gnomad FIN exome

AF:

0.0476

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0314

GnomAD4 exome

AF:

0.0259

AC:

37728

AN:

1454224

Hom.:

664

Cov.:

AF XY:

0.0261

AC XY:

18861

AN XY:

723214

show subpopulations

Gnomad4 AFR exome

AF:

0.00461

Gnomad4 AMR exome

AF:

0.0322

Gnomad4 ASJ exome

AF:

0.0152

Gnomad4 EAS exome

AF:

0.0913

Gnomad4 SAS exome

AF:

0.0281

Gnomad4 FIN exome

AF:

0.0490

Gnomad4 NFE exome

AF:

0.0230

Gnomad4 OTH exome

AF:

0.0264

GnomAD4 genome

AF:

0.0232

AC:

3523

AN:

151818

Hom.:

Cov.:

AF XY:

0.0239

AC XY:

1772

AN XY:

74188

show subpopulations

Gnomad4 AFR

AF:

0.00495

Gnomad4 AMR

AF:

0.0252

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.0942

Gnomad4 SAS

AF:

0.0312

Gnomad4 FIN

AF:

0.0450

Gnomad4 NFE

AF:

0.0247

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0172

Hom.:

Bravo

AF:

0.0209

Asia WGS

AF:

0.0490

AC:

168

AN:

3476

EpiCase

AF:

0.0226

EpiControl

AF:

0.0241

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

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

Invitae

Feb 01, 2024

- -

Early-onset myopathy with fatal cardiomyopathy

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

- -

Myopathy, myofibrillar, 9, with early respiratory failure

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

-0.68

Cadd

Benign

0.0040

Dann

Benign

0.74

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