rs727503706

Variant names:

• chr2-178794448-G-A
• rs727503706
• NM_001267550.2:c.1349C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001267550.2(TTN):​c.1349C>T​(p.Ala450Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34369618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.1349C>T	p.Ala450Val	missense_variant	Exon 8 of 363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.1349C>T	p.Ala450Val	missense_variant	Exon 8 of 46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.1349C>T	p.Ala450Val	missense_variant	Exon 8 of 363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.1349C>T	p.Ala450Val	missense_variant	Exon 8 of 46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251366 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 14, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala450Val variant in TTN has not been previously reported in individuals wit h cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, the clinical significance of the Ala450Val variant is uncertain. -

Cardiomyopathy Uncertain:1

Oct 01, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N;N;.;.;N;N;.;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.011	D;D;.;.;D;D;.;D;D
Sift4G	Uncertain	0.0060	.;.;.;.;.;.;.;D;.
Polyphen		0.99, 1.0	.;.;.;D;.;.;D;D;.
Vest4		0.35
MutPred		0.50		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);.;
MVP		0.51
MPC		0.42
ClinPred		0.51	D
GERP RS		5.6

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: rs727503706; hg19: chr2-179659175; COSMIC: COSV100588973; COSMIC: COSV100588973;