rs200161147

chr2-178689055-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.32093G>A(p.Arg10698Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,551,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R10698R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Scores: Splicing: ADA: 0.0003487
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5 O:1
• Conservation: PhyloP100: 0.484

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]

LOC124907912 (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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.026729286).
• BP6: Variant 2-178689055-C-T is Benign according to our data. Variant chr2-178689055-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202570.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, not_provided=1, Likely_benign=3}. Variant chr2-178689055-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.32093G>A	p.Arg10698Gln	missense_variant, splice_region_variant	125/363	ENST00000589042.5
LOC124907912	XR_007087321.1	n.918C>T		non_coding_transcript_exon_variant	1/2
LOC124906100	XR_007087318.1	n.2186-24699C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.32093G>A	p.Arg10698Gln	missense_variant, splice_region_variant	125/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-45449C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000358 AC: 50 AN: 139784 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000303

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000688

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000454

Gnomad OTH AF: 0.000530

GnomAD3 exomes AF: 0.000239 AC: 59 AN: 247318 Hom.: 0 AF XY: 0.000298 AC XY: 40 AN XY: 134230

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.000920

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000115 AC: 162 AN: 1411222 Hom.: 0 Cov.: 35 AF XY: 0.000138 AC XY: 97 AN XY: 704156

Gnomad4 AFR exome AF: 0.00154

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.000353

Gnomad4 EAS exome AF: 0.0000772

Gnomad4 SAS exome AF: 0.000743

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000137

GnomAD4 genome AF: 0.000358 AC: 50 AN: 139854 Hom.: 0 Cov.: 27 AF XY: 0.000314 AC XY: 21 AN XY: 66912

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.000302

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000691

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000454

Gnomad4 OTH AF: 0.000526

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000374

ESP6500AA AF: 0.000817 AC: 3

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000257 AC: 31

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2018	- -
not provided, no classification provided	clinical testing	GeneDx	Apr 14, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TTN: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Arg9454Gln va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.1% (19/16434) of South Asian chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20016 1147). Arginine (Arg) at position 9454 is not conserved in mammals or evolutiona rily distant species and 1 mammal (weddell seal) carries a glutamine (Gln) at th is position, raising the possibility that this change may be tolerated. In addit ion, this variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicin g. However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg9454Gln variant is unce rtain, it's frequency and the presence of the variant amino acid in another mamm al suggest it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 22, 2021	- -

TTN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2023

The TTN c.32093G>A variant is predicted to result in the amino acid substitution p.Arg10698Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179553782-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 21, 2017

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.070
Eigen_PC	Benign	0.051
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.57	T;T;.;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N;.;.;.;N
REVEL	Benign	0.034
Sift	Benign	0.11	T;.;.;.;T
Polyphen		0.20	.;.;B;B;.
Vest4		0.30
MVP		0.16
MPC		0.10
ClinPred		0.013	T
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.026
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: rs200161147; hg19: chr2-179553782; COSMIC: COSV104641658;