2-178540091-G-C

Variant names:

• chr2-178540091-G-C
• rs727505311
• NM_001267550.2:c.98075C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001267550.2(TTN):​c.98075C>G​(p.Thr32692Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000193 in 1,453,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.67
• Publications: 0 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-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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28269693).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.98075C>G	p.Thr32692Arg	missense	Exon 351 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.93152C>G	p.Thr31051Arg	missense	Exon 301 of 313	NP_001243779.1
	TTN	NM_133378.4		c.90371C>G	p.Thr30124Arg	missense	Exon 300 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.98075C>G	p.Thr32692Arg	missense	Exon 351 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.97919C>G	p.Thr32640Arg	missense	Exon 349 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.97799C>G	p.Thr32600Arg	missense	Exon 349 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000327 AC: 8 AN: 244428 AF XY: 0.0000377

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000526

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 28 AN: 1453780 Hom.: 0 Cov.: 32 AF XY: 0.0000222 AC XY: 16 AN XY: 722044

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.000546 AC: 14 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 85330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1106700

Other (OTH) AF: 0.00 AC: 0 AN: 60012

GnomAD4 genome Cov.: 32

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr30124Arg variant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein. In summary, the clinical significance of the p.Thr30124Arg variant is uncertain.

TTN-related disorder Uncertain:1

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TTN c.98075C>G variant is predicted to result in the amino acid substitution p.Thr32692Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.053% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. 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.

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

Oct 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Jun 27, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.82
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.22
Sift	Benign	0.049	D
Polyphen		0.97	D
Vest4		0.52
MutPred		0.39		Loss of glycosylation at T31051 (P = 0.0224)
MVP		0.67
MPC		0.34
ClinPred		0.25	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=65/35	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: rs727505311; hg19: chr2-179404818;