2-178649817-C-T

Variant names:

• chr2-178649817-C-T
• rs758166967
• NM_001267550.2:c.39895G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001267550.2(TTN):​c.39895G>A​(p.Glu13299Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTN NM_001267550.2 missense
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92
• Publications: 2 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.39895G>A	p.Glu13299Lys	missense_variant	Exon 211 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.39895G>A	p.Glu13299Lys	missense_variant	Exon 211 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu10865L ys variant in TTN has not been previously reported in individuals with cardiomyo pathy or in large population studies. This variant changes an amino acid but is also located in the last base of the exon, which is part of the 5? splice region . It is predicted to abolish splicing by computational tools but their accuracy is not known. In summary, while there is some suspicion for a pathogenic role, t he clinical significance of the p.Glu10865Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T;.;T;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	.;.;L;L;.
PhyloP100		1.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N;.;.;.;N
REVEL	Benign	0.050
Sift	Benign	0.17	T;.;.;.;T
Polyphen		0.083	.;.;B;B;.
Vest4		0.12
MutPred		0.33		.;.;Gain of methylation at E11792 (P = 0.0042);Gain of methylation at E11792 (P = 0.0042);.;
MVP		0.41
MPC		0.098
ClinPred		0.69	D
GERP RS		5.6
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.54		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758166967; hg19: chr2-179514544;