rs200875815

Positions:

• chr2-178769694-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_001267550.2(TTN):​c.8887A>C​(p.Thr2963Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.89

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 -11 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=0.0024864674).
• BP6: Variant 2-178769694-T-G is Benign according to our data. Variant chr2-178769694-T-G is described in ClinVar as [Benign]. Clinvar id is 137826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178769694-T-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.8887A>C	p.Thr2963Pro	missense_variant	37/363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.8887A>C	p.Thr2963Pro	missense_variant	37/46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.8887A>C	p.Thr2963Pro	missense_variant	37/363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.8887A>C	p.Thr2963Pro	missense_variant	37/46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 309 AN: 151062 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000790

Gnomad ASJ AF: 0.00522

Gnomad EAS AF: 0.00292

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.000571

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00338

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0234 AC: 33711 AN: 1442314 Hom.: 0 Cov.: 33 AF XY: 0.0284 AC XY: 20354 AN XY: 716000

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.0943

Gnomad4 ASJ exome AF: 0.0523

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.0693

Gnomad4 FIN exome AF: 0.0872

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00207 AC: 313 AN: 151146 Hom.: 0 Cov.: 32 AF XY: 0.00256 AC XY: 189 AN XY: 73750

Gnomad4 AFR AF: 0.000387

Gnomad4 AMR AF: 0.000790

Gnomad4 ASJ AF: 0.00522

Gnomad4 EAS AF: 0.00273

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000571

Gnomad4 NFE AF: 0.00346

Gnomad4 OTH AF: 0.00430

Alfa AF: 0.00557 Hom.: 0

ExAC AF: 0.355 AC: 38310

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2012	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. -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Benign	0.94
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;.;D;D;D;D
MetaRNN	Benign	0.0025	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.16	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.1	D;D;.;.;D;D;.;D
REVEL	Pathogenic	0.70
Sift	Benign	0.12	T;T;.;.;T;T;.;D
Sift4G	Uncertain	0.0090	.;.;.;.;.;.;.;D
Polyphen		1.0	.;.;.;D;.;.;D;D
Vest4		0.19
MPC		0.53
ClinPred		0.035	T
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200875815; hg19: chr2-179634421; COSMIC: COSV59871240; COSMIC: COSV59871240;