2-178664926-G-C

Position:

• chr2-178664926-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001267550.2(TTN):​c.36044C>G​(p.Thr12015Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,604,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T12015M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Scores: Splicing: ADA: 0.00005145
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.401

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
• BP4: Computational evidence support a benign effect (MetaRNN=0.034800023).
• BP6: Variant 2-178664926-G-C is Benign according to our data. Variant chr2-178664926-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191988.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr2-178664926-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.36044C>G	p.Thr12015Arg	missense_variant, splice_region_variant	166/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+20425G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.36044C>G	p.Thr12015Arg	missense_variant, splice_region_variant	166/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+67245G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152078 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000213 AC: 47 AN: 220756 Hom.: 0 AF XY: 0.000198 AC XY: 24 AN XY: 121228

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.000361 AC: 524 AN: 1452712 Hom.: 0 Cov.: 32 AF XY: 0.000341 AC XY: 246 AN XY: 721770

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000368

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000447

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152078 Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74286

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000283

ESP6500AA AF: 0.000571 AC: 1

ESP6500EA AF: 0.000251 AC: 1

ExAC AF: 0.000200 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TTN: BP4 -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 02, 2020	The TTN c.36044C>G; p.Thr12015Arg variant (rs199868380; ClinVar Variation ID: 191988) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Thr12015Arg variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 06, 2023

Variant summary: TTN c.31484-1871C>G is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 220756 control chromosomes (gnomAD). c.31484-1871C>G has been reported in the literature in one individual affected with sudden arrhythmic death syndrome (Andersen_2019). The report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31392414). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.96
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
Vest4		0.16
MVP		0.56
MPC		0.096
ClinPred		0.030	T
GERP RS		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.10
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: rs199868380; hg19: chr2-179529653;