chr2-178718746-C-T

Position:

• chr2-178718746-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_001267550.2(TTN):​c.24454G>A​(p.Val8152Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.11

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 Likely_benign. Variant got -2 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=0.09499732).
• BP6: Variant 2-178718746-C-T is Benign according to our data. Variant chr2-178718746-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46732.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr2-178718746-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.24454G>A	p.Val8152Ile	missense_variant	84/363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.24454G>A	p.Val8152Ile	missense_variant	84/363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000563 AC: 14 AN: 248596 Hom.: 0 AF XY: 0.0000742 AC XY: 10 AN XY: 134856

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461514 Hom.: 0 Cov.: 37 AF XY: 0.0000523 AC XY: 38 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152094 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74302

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 12, 2023	Variant summary: TTN c.20722G>A (p.Val6908Ile) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 326038 control chromosomes, predominantly at a frequency of 0.0011 within the Japanese subpopulation, including 1 homozygote (gnomAD and jMorp databases; Tadaka_2021). The observed variant frequency is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing a dilated cardiomyopathy phenotype (3.9e-04), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.20722G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (ALMS1 c.427C>T, p.Q143X; MYH7 c.4259G>A, p.R1420Q; both observed in internal testing), providing supporting evidence for a benign role. The following publication was ascertained in the context of this evaluation (PMID: 33179747). Two ClinVar submitters (evaluation after 2014) have cited the variant; one submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Val6908Ile va riant in TTN has been identified by our laboratory in 1 adult with HCM, who also carried an pathogenic HCM variant. The Val6908Ile variant has been identified i n 2/16502 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs397517507). Valine (Val) at position 6908 i s not conserved in evolution and several species have an isoleucine (Ile) at thi s position, suggesting that this change may be tolerated. In summary, while the clinical significance of the p.Val6908Ile variant is uncertain, the presence of the variant amino acid in other species suggests that it is more likely to be be nign. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2013

There is insufficient or conflicting evidence for classification of this alteration. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.92
Eigen	Benign	-0.10
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.65	T;T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-0.62	T
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.45	N;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.36	T;.;.;.
Polyphen		0.018	.;.;B;B
Vest4		0.050
MutPred		0.71		.;.;Loss of catalytic residue at V7835 (P = 0.0235);Loss of catalytic residue at V7835 (P = 0.0235);
MVP		0.42
MPC		0.072
ClinPred		0.022	T
GERP RS		6.0

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: rs397517507; hg19: chr2-179583473; COSMIC: COSV60334381; COSMIC: COSV60334381;