rs139669372

Positions:

• chr2-178748156-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_133379.5(TTN):​c.14244T>C​(p.Leu4748Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,192 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (134 hom.)
• Consequence: TTN NM_133379.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.00

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-178748156-A-G is Benign according to our data. Variant chr2-178748156-A-G is described in ClinVar as [Benign]. Clinvar id is 47769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178748156-A-G is described in Lovd as [Benign]. Variant chr2-178748156-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00776 (1180/152140) while in subpopulation NFE AF= 0.0127 (863/67964). AF 95% confidence interval is 0.012. There are 9 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_133379.5	c.14244T>C	p.Leu4748Leu	synonymous_variant	46/46	ENST00000360870.10	NP_596870.2
TTN	NM_001267550.2	c.11311+4968T>C		intron_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000360870.10	c.14244T>C	p.Leu4748Leu	synonymous_variant	46/46	5	NM_133379.5	ENSP00000354117.4
TTN	ENST00000589042.5	c.11311+4968T>C		intron_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1181 AN: 152022 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00764 AC: 1906 AN: 249516 Hom.: 13 AF XY: 0.00748 AC XY: 1011 AN XY: 135192

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.00894

GnomAD4 exome AF: 0.0118 AC: 17170 AN: 1461052 Hom.: 134 Cov.: 35 AF XY: 0.0113 AC XY: 8237 AN XY: 726822

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00395

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.00776 AC: 1180 AN: 152140 Hom.: 9 Cov.: 32 AF XY: 0.00710 AC XY: 528 AN XY: 74364

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00368

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00960

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.0102 Hom.: 3

Bravo AF: 0.00777

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0125

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TTN: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2013	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	Dec 09, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.65

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

Other links and lift over

dbSNP: rs139669372; hg19: chr2-179612883;