2-178790082-T-C

Variant names:

• chr2-178790082-T-C
• rs727505256
• NM_001267550.2:c.1834A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.1834A>G​(p.Lys612Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,612,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.87
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1G

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset myopathy with fatal cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• TTN-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopathy, myofibrillar, 9, with early respiratory failure

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• tibial muscular dystrophy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• autosomal recessive limb-girdle muscular dystrophy type 2J

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hypertrophic cardiomyopathy 9

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital myopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary skeletal muscle disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032369256).
• BP6: Variant 2-178790082-T-C is Benign according to our data. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976. Variant chr2-178790082-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 179976.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.1834A>G	p.Lys612Glu	missense_variant	Exon 12 of 363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.1834A>G	p.Lys612Glu	missense_variant	Exon 12 of 46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.1834A>G	p.Lys612Glu	missense_variant	Exon 12 of 363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.1834A>G	p.Lys612Glu	missense_variant	Exon 12 of 46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

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

GnomAD2 exomes AF: 0.0000916 AC: 23 AN: 251028 AF XY: 0.0000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1460798 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 726740

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111390

Other (OTH) AF: 0.0000663 AC: 4 AN: 60348

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Jan 02, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 27, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Lys612Glu variant in TTN has not been previously reported in individuals wit h cardiomyopathy and was absent from large population studies. Computational pre diction tools and conservation analysis suggest this variant may not impact the protein, though this information is not predictive enough to rule out pathogenic ity. In summary, the clinical significance of the Lys612Glu variant is uncertain . -

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 25, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.97
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;T;T;.;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.032	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
PhyloP100		1.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N;N;.;.;N;N;.;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;.;.;D;D;.;D
Sift4G	Benign	0.11	.;.;.;.;.;.;.;T
Polyphen		0.26, 0.91	.;.;.;B;.;.;B;P
Vest4		0.30
MVP		0.20
MPC		0.18
ClinPred		0.17	T
GERP RS		4.7
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs727505256; hg19: chr2-179654809; COSMIC: COSV60111066;