rs535294541

Positions:

• chr2-178662748-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001267550.2(TTN):​c.36855G>A​(p.Pro12285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (59 hom., cov: 18)
  • Exomes 𝑓: 0.010 (109 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.05

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-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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-178662748-C-T is Benign according to our data. Variant chr2-178662748-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178662748-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.05 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.36855G>A	p.Pro12285=	synonymous_variant	175/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2185+18247C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.36855G>A	p.Pro12285=	synonymous_variant	175/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+65067C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2884 AN: 130048 Hom.: 59 Cov.: 18 FAILED QC

Gnomad AFR AF: 0.0570

Gnomad AMI AF: 0.00607

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.00379

Gnomad EAS AF: 0.00732

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0238

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0167 AC: 955 AN: 57318 Hom.: 15 AF XY: 0.0163 AC XY: 466 AN XY: 28676

Gnomad AFR exome AF: 0.0633

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.00508

Gnomad EAS exome AF: 0.00608

Gnomad SAS exome AF: 0.0195

Gnomad FIN exome AF: 0.00809

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.0176

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0105 AC: 12724 AN: 1217584 Hom.: 109 Cov.: 17 AF XY: 0.0106 AC XY: 6438 AN XY: 608696

Gnomad4 AFR exome AF: 0.0623

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.00474

Gnomad4 EAS exome AF: 0.00341

Gnomad4 SAS exome AF: 0.0178

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00827

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0222 AC: 2894 AN: 130134 Hom.: 59 Cov.: 18 AF XY: 0.0223 AC XY: 1387 AN XY: 62206

Gnomad4 AFR AF: 0.0573

Gnomad4 AMR AF: 0.0200

Gnomad4 ASJ AF: 0.00379

Gnomad4 EAS AF: 0.00712

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.00735

Gnomad4 OTH AF: 0.0247

Alfa AF: 0.0168 Hom.: 4

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

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

-

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 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	-0.70
CADD	Benign	0.69
DANN	Benign	0.86

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

Other links and lift over

dbSNP: rs535294541; hg19: chr2-179527475;