chr2-178625296-G-A

Variant names:

• chr2-178625296-G-A
• rs370782364
• NM_001267550.2:c.44525C>T

Variant summary

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

The NM_001267550.2(TTN):​c.44525C>T​(p.Thr14842Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000481 in 1,455,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.47
• 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=0.3361381).

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.44525C>T	p.Thr14842Ile	missense	Exon 241 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.39602C>T	p.Thr13201Ile	missense	Exon 191 of 313	NP_001243779.1
	TTN	NM_133378.4		c.36821C>T	p.Thr12274Ile	missense	Exon 190 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.44525C>T	p.Thr14842Ile	missense	Exon 241 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.44369C>T	p.Thr14790Ile	missense	Exon 239 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.44249C>T	p.Thr14750Ile	missense	Exon 239 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 244468 AF XY: 0.00

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455132 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 723854

African (AFR) AF: 0.000121 AC: 4 AN: 32952

American (AMR) AF: 0.00 AC: 0 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39298

South Asian (SAS) AF: 0.00 AC: 0 AN: 85380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108804

Other (OTH) AF: 0.00 AC: 0 AN: 60082

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000271 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Nov 07, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Aug 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.95
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.50
MVP		0.31
MPC		0.36
ClinPred		0.37	T
GERP RS		6.0
Mutation Taster		=76/24	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: rs370782364; hg19: chr2-179490023;