chr2-178593006-G-A

Position:

• chr2-178593006-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BP6

The NM_001267550.2(TTN):​c.59113C>T​(p.Arg19705Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000214 in 1,613,342 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19705H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 4.28

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]

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=0.34869993).
• BP6: Variant 2-178593006-G-A is Benign according to our data. Variant chr2-178593006-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47146.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr2-178593006-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.59113C>T	p.Arg19705Cys	missense_variant	300/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.3364+1692G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.59113C>T	p.Arg19705Cys	missense_variant	300/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-4590G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000238 AC: 59 AN: 248286 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134668

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000212 AC: 310 AN: 1461244 Hom.: 0 Cov.: 35 AF XY: 0.000216 AC XY: 157 AN XY: 726916

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74304

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000349 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000207 AC: 25

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	This variant is associated with the following publications: (PMID: 30924900, 26567375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 20, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 31, 2022	Variant summary: TTN c.51409C>T (p.Arg17137Cys) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 248286 control chromosomes, predominantly at a frequency of 0.00044 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.51409C>T has been reported in the literature in individuals affected with different Cardiomyopathies (Begay_2015, Klauke_2017). In a family reported by Klauke_2017, two sisters with arrhythmogenic right ventricular cardiomyopathy were genotyped; one sister carried this variant and the other sister carried the reference allele, showing the variant did not segregate with the disease phenotype. These siblings also carried other pathogenic variants (PLN c.40_42delAGA, p.Arg14del) which segregated with disease, providing supporting evidence for a benign role of TTN c.51409C>T. An undisclosed pathogenic co-occurence was also reported by ClinVar submitter "Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine" (Accession: SCV000064107.7). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and two as likely benign. 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	Dec 20, 2019	The p.Arg17137Cys variant in TTN has been identified by our laboratory in 1 African American individual with RCM and a dilated left atrium who also carried a pathogenic variant in another gene that most likely explained their disease. This variant has also been identified in 0.04% (15/35302) of Latino chromosomes by the gnomAD (https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg17137Cys variant is uncertain. -

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

Dec 13, 2017

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 05, 2018

- -

Arrhythmogenic right ventricular dysplasia 9 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

May 01, 2016

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2019

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	Benign	0.23
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Benign	0.85
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.6	.;.;.;L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.8	D;D;.;.;D;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D;D;.;.;D;D;.
Polyphen		1.0	.;.;.;D;.;.;D
Vest4		0.59
MVP		0.38
MPC		0.50
ClinPred		0.094	T
GERP RS		6.2

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: rs72646839; hg19: chr2-179457733; COSMIC: COSV60395344; COSMIC: COSV60395344;