2-178784351-C-T

Variant names:

• chr2-178784351-C-T
• rs376133574
• NM_001267550.2:c.2494G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001267550.2(TTN):​c.2494G>A​(p.Ala832Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. A832S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-178784351-C-A is described in Lovd as [Likely_pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.2494G>A	p.Ala832Thr	missense_variant, splice_region_variant	Exon 16 of 363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.2494G>A	p.Ala832Thr	missense_variant, splice_region_variant	Exon 16 of 46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.2494G>A	p.Ala832Thr	missense_variant, splice_region_variant	Exon 16 of 363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.2494G>A	p.Ala832Thr	missense_variant, splice_region_variant	Exon 16 of 46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;D;D;D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N;N;.;.;N;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.045	D;T;.;.;D;D;.;D
Sift4G	Benign	0.099	.;.;.;.;.;.;.;T
Polyphen		0.18, 0.87	.;.;.;B;.;.;B;P
Vest4		0.36
MutPred		0.27		Gain of phosphorylation at A832 (P = 0.0786);.;Gain of phosphorylation at A832 (P = 0.0786);Gain of phosphorylation at A832 (P = 0.0786);.;.;Gain of phosphorylation at A832 (P = 0.0786);Gain of phosphorylation at A832 (P = 0.0786);
MVP		0.32
MPC		0.092
ClinPred		0.66	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.010		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: rs376133574; hg19: chr2-179649078;