rs776115575

Positions:

• chr2-178642284-A-C
• chr2-178642284-A-G

Variant summary

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

The NM_001267550.2(TTN):​c.40511T>G​(p.Leu13504Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000097 in 1,443,782 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000097 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.14

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: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]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 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=0.2429179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.40511T>G	p.Leu13504Arg	missense_variant	219/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.40511T>G	p.Leu13504Arg	missense_variant	219/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+44603A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000268 AC: 6 AN: 224074 Hom.: 0 AF XY: 0.00000827 AC XY: 1 AN XY: 120954

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000970 AC: 14 AN: 1443782 Hom.: 1 Cov.: 30 AF XY: 0.00000977 AC XY: 7 AN XY: 716632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000145

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.07e-7

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000416 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 24, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	.;.;.;.;.;.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T;T;.;T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.;M;.
MutationTaster	Benign	0.57	D;D;D;D;D;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.2	D;D;.;.;D;D;.;D
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D;D;.;.;D;D;.;D
Polyphen		0.97	.;.;.;D;.;.;D;.
Vest4		0.45
MutPred		0.25		.;.;.;Gain of MoRF binding (P = 0.013);.;.;Gain of MoRF binding (P = 0.013);.;
MVP		0.63
MPC		0.39
ClinPred		0.58	D
GERP RS		5.5

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: rs776115575; hg19: chr2-179507011;