2-178617838-C-T

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.47513G>A(p.Arg15838Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,612,424 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 2.47

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 where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.05563882).
• BP6: Variant 2-178617838-C-T is Benign according to our data. Variant chr2-178617838-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195546.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=3, Benign=1}. Variant chr2-178617838-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.47513G>A	p.Arg15838Gln	missense_variant	253/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.47513G>A	p.Arg15838Gln	missense_variant	253/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+20157C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151934 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000278 AC: 69 AN: 247874 Hom.: 0 AF XY: 0.000297 AC XY: 40 AN XY: 134472

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000500

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000489 AC: 714 AN: 1460490 Hom.: 1 Cov.: 32 AF XY: 0.000478 AC XY: 347 AN XY: 726566

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000591

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000250 AC: 38 AN: 151934 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74194

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000431 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000512 AC: 2

ESP6500EA AF: 0.000601 AC: 5

ExAC AF: 0.000339 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2023	Variant summary: TTN c.39809G>A (p.Arg13270Gln) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 247874 control chromosomes, predominantly at a frequency of 0.0005 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.39809G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported via internal testing (MYBPC3 c.2374T>C, p.W792R), providing supporting evidence for a benign role. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as VUS (n=6) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 26, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Arg13270Gln v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 32/66627 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199640194). Argin ine (Arg) at position 39809 is not conserved in evolutionarily distant species a nd 5 different reptile species carry a Glutamine (Gln), raising the possibility that this change may be tolerated. Additional computational prediction tools sug gest that the p.Arg13270Gln variant may not impact the protein, though this info rmation is not predictive enough to rule out pathogenicity. In summary, while th e clinical significance of the p.Arg13270Gln variant is uncertain, these data su ggest that it is more likely to be benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2017

- -

Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 17, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 08, 2022

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2020

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	0.098
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	24
Dann	Benign	0.97
Eigen	Benign	-0.031
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.056	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N;N;.;.;N;N;.
REVEL	Benign	0.082
Sift	Benign	0.32	T;T;.;.;T;T;.
Polyphen		0.054	.;.;.;B;.;.;B
Vest4		0.20
MVP		0.13
MPC		0.099
ClinPred		0.023	T
GERP RS		5.6

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: rs199640194; hg19: chr2-179482565; COSMIC: COSV59953778; COSMIC: COSV59953778;