rs727503588

chr2-178591978-G-A

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.59926C>T(p.His19976Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000341 in 1,611,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Scores: Splicing: ADA: 0.0007304
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 4.41

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=0.047986746).
• BP6: Variant 2-178591978-G-A is Benign according to our data. Variant chr2-178591978-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165933.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.59926C>T	p.His19976Tyr	missense_variant, splice_region_variant	302/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.3364+664G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.59926C>T	p.His19976Tyr	missense_variant, splice_region_variant	302/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-5618G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000528 AC: 13 AN: 246042 Hom.: 0 AF XY: 0.0000449 AC XY: 6 AN XY: 133482

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000283

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 49 AN: 1459186 Hom.: 0 Cov.: 35 AF XY: 0.0000276 AC XY: 20 AN XY: 725772

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74392

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000414 AC: 5

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2019	The c.52222C>T; p.His17408Tyr variant (rs727503588) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall frequency of 0.03 percent in the East Asian population (identified on 6 out of 19,198 chromosomes). This variant is directly 5' to a canonical donor splice site, and though a variant of this adjacent base has been reported in dilated cardiomyopathy, the c.52222C>T has not been reported. This missense variant affects a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical splice site. Without functional mRNA splicing however, the p.His17408Tyr variant cannot be classified with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2014	Variant classified as Uncertain Significance - Favor Benign. The His17408Tyr var iant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. It should be noted th at several other species (armadillo, green seaturtle, painted turtle, and 5 fish es) carry a tyrosine (Tyr) at this position, suggesting that this change may be tolerated. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not predict altered splici ng, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the His17408Tyr variant is uncert ain, the presence of this variant in other species suggests that it is more like ly to be benign. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 28, 2021	- -

TTN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2022

The TTN c.59926C>T variant is predicted to result in the amino acid substitution p.His19976Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.031% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179456705-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2016

- -

Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 28, 2022

The c.59926C>T (p.His19976Tyr) missense variant identified in the TTN gene has not been reported in affected individuals in the literature. The variant has 0.00003946 allele frequency in the gnomAD (v3.1.2) database (6 out of 152058 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The variant has been reported in the ClinVar database as a variant of uncertain significance (4 entries) and likely benign (2 entries) (Variation ID: 165933). The variant affects a moderately conserved residue (His19976) located in the A-band domain of the TTN gene (PMID: 25589632). The TTN gene has 363 exons (transcript NM_001267550.2), and this variant alters the last nucleotide of exon 302 suggesting that it may affect the normal mRNA splicing. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 22.5,REVEL score = 0.082, Splice AI = 0.00, TRAP = 0.551]. Based on the available evidence, the c.59926C>T (p.His19976Tyr) missense variant identified in the TTN gene is reported as a Variant of Uncertain Significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 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	0.091
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	18
Dann	Benign	0.89
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T;T;T;.;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.048	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.96	D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D;D;.;.;D;D;.
REVEL	Benign	0.082
Sift	Benign	0.83	T;T;.;.;T;T;.
Polyphen		0.0010	.;.;.;B;.;.;B
Vest4		0.36
MutPred		0.34		.;.;.;Gain of phosphorylation at H18335 (P = 0.0227);.;.;Gain of phosphorylation at H18335 (P = 0.0227);
MVP		0.10
MPC		0.097
ClinPred		0.042	T
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00073
dbscSNV1_RF	Benign	0.066
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: rs727503588; hg19: chr2-179456705;