Genetic Variant NM_001267550.2:c.56573G>T (chr2-178599220-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001267550.2(TTN):c.56573G>T(p.Arg18858Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18858Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.12

Publications

2 publications found

Variant links:

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 links:

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]

TTN-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.772

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.56573G>T	p.Arg18858Leu	missense	Exon 290 of 363	NP_001254479.2
TTN	NM_001256850.1		c.51650G>T	p.Arg17217Leu	missense	Exon 240 of 313	NP_001243779.1
TTN	NM_133378.4		c.48869G>T	p.Arg16290Leu	missense	Exon 239 of 312	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.56573G>T	p.Arg18858Leu	missense	Exon 290 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.56417G>T	p.Arg18806Leu	missense	Exon 288 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.56297G>T	p.Arg18766Leu	missense	Exon 288 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1376898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676834

African (AFR)

AF:

0.00

AC:

AN:

30464

American (AMR)

AF:

0.00

AC:

AN:

30696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21014

East Asian (EAS)

AF:

0.00

AC:

AN:

38550

South Asian (SAS)

AF:

0.00

AC:

AN:

68408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5376

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074940

Other (OTH)

AF:

0.00

AC:

AN:

56782

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.97

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.036

MutationAssessor

Pathogenic

3.5

PhyloP100

6.1

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

Polyphen

0.98

Vest4

0.62

MutPred

0.71

Loss of catalytic residue at R17217 (P = 0.0117)

MVP

0.70

MPC

0.42

ClinPred

0.94

GERP RS

5.1

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over