rs762149243

Positions:

• chr2-178662539-C-T

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.36952G>A​(p.Val12318Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (73 hom., cov: 9)
  • Exomes 𝑓: 0.0023 (145 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.95

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=0.0030481815).
• BP6: Variant 2-178662539-C-T is Benign according to our data. Variant chr2-178662539-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238757.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr2-178662539-C-T is described in Lovd as [Benign]. Variant chr2-178662539-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.36952G>A	p.Val12318Ile	missense_variant	176/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+18038C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.36952G>A	p.Val12318Ile	missense_variant	176/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+64858C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1204 AN: 69592 Hom.: 72 Cov.: 9 FAILED QC

Gnomad AFR AF: 0.0750

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00626

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: 0.000283

Gnomad OTH AF: 0.00854

GnomAD3 exomes AF: 0.00984 AC: 432 AN: 43918 Hom.: 46 AF XY: 0.00749 AC XY: 168 AN XY: 22426

Gnomad AFR exome AF: 0.0927

Gnomad AMR exome AF: 0.00338

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: 0.000277

Gnomad OTH exome AF: 0.00252

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00235 AC: 2272 AN: 967422 Hom.: 145 Cov.: 13 AF XY: 0.00206 AC XY: 993 AN XY: 483146

Gnomad4 AFR exome AF: 0.0918

Gnomad4 AMR exome AF: 0.00448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000722

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0174 AC: 1212 AN: 69626 Hom.: 73 Cov.: 9 AF XY: 0.0160 AC XY: 508 AN XY: 31668

Gnomad4 AFR AF: 0.0752

Gnomad4 AMR AF: 0.00626

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000283

Gnomad4 OTH AF: 0.00843

Alfa AF: 0.0255 Hom.: 15

ExAC AF: 0.00255 AC: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2017

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.70
DANN	Benign	0.74
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
Vest4		0.074
ClinPred		0.0060	T
GERP RS		-0.15

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: rs762149243; hg19: chr2-179527266;