rs201674674

Positions:

• chr2-178561209-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001267550.2(TTN):​c.84923A>C​(p.Gln28308Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,613,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2 O:1
• Conservation: PhyloP100: 1.66

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 -4 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=0.04057786).
• BP6: Variant 2-178561209-T-G is Benign according to our data. Variant chr2-178561209-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47441.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.84923A>C	p.Gln28308Pro	missense_variant	326/363	ENST00000589042.5	NP_001254479.2
TTN-AS1	NR_038272.1	n.2043+18848T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.84923A>C	p.Gln28308Pro	missense_variant	326/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.417-36387T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000206 AC: 51 AN: 248134 Hom.: 0 AF XY: 0.000201 AC XY: 27 AN XY: 134602

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000365

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000265 AC: 387 AN: 1461312 Hom.: 1 Cov.: 32 AF XY: 0.000270 AC XY: 196 AN XY: 726942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74444

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000873

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 19, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 28, 2023	- -
not provided, no classification provided	clinical testing	GeneDx	Aug 28, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Jan 04, 2018

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2018

The p.Q19243P variant (also known as c.57728A>C), located in coding exon 153 of the TTN gene, results from an A to C substitution at nucleotide position 57728. The glutamine at codon 19243 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, proline is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 28, 2014

Gln25740Pro in exon 275 of TTN: This variant has been identified in 1/8250 Europ ean American chromosomes and 1/3832 African American chromosomes by the NHLBI Ex ome Sequencing Project (http://evs.gs.washington.edu/EVS/). It is not expected t o have clinical significance due to a lack of evolutionary conservation. Of note , 5 have a proline (Pro) at this position despite high nearby amino acid conserv ation, suggesting that this change is tolerated. -

Congestive heart failure Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.69
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T;T;T;.;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.041	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.18	.;.;.;N;.;.;N
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.2	D;D;.;.;D;D;.
REVEL	Benign	0.12
Sift	Benign	0.16	T;T;.;.;T;T;.
Polyphen		0.0	.;.;.;B;.;.;B
Vest4		0.55
MVP		0.10
MPC		0.10
ClinPred		0.038	T
GERP RS		0.31

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: rs201674674; hg19: chr2-179425936;