2-178578812-G-A

Position:

• chr2-178578812-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BP6

The NM_001267550.2(TTN):​c.68218C>T​(p.Pro22740Ser) variant causes a missense 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P22740P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 9.94

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]

(HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.29487857).
• BP6: Variant 2-178578812-G-A is Benign according to our data. Variant chr2-178578812-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264208.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.68218C>T	p.Pro22740Ser	missense_variant	320/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.2044-3760G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.68218C>T	p.Pro22740Ser	missense_variant	320/363	5	NM_001267550.2	P1
	ENST00000603521.1	n.23G>A		non_coding_transcript_exon_variant	1/1
TTN-AS1	ENST00000659121.1	n.417-18784G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 24, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.93
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.4	.;.;.;M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.1	D;D;.;.;D;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D;D;.;.;D;D;.
Polyphen		0.97	.;.;.;D;.;.;D
Vest4		0.34
MutPred		0.35		.;.;.;Gain of phosphorylation at P21099 (P = 0.0222);.;.;Gain of phosphorylation at P21099 (P = 0.0222);
MVP		0.28
MPC		0.27
ClinPred		0.49	T
GERP RS		5.7

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: rs886039082; hg19: chr2-179443539;