chr2-178619748-A-T

Variant names:

• chr2-178619748-A-T
• rs1553713980
• NM_001267550.2:c.46569T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.46569T>A​(p.Asp15523Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D15523D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.576
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21946251).

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.46569T>A	p.Asp15523Glu	missense	Exon 250 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.41646T>A	p.Asp13882Glu	missense	Exon 200 of 313	NP_001243779.1
	TTN	NM_133378.4		c.38865T>A	p.Asp12955Glu	missense	Exon 199 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.46569T>A	p.Asp15523Glu	missense	Exon 250 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.46413T>A	p.Asp15471Glu	missense	Exon 248 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.46293T>A	p.Asp15431Glu	missense	Exon 248 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460502 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726562

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111070

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 15, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Feb 13, 2025

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	0.27
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.83
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.58
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.27
Sift	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.48		Gain of methylation at K13883 (P = 0.0817)
MVP		0.36
MPC		0.45
ClinPred		0.32	T
GERP RS		-0.040
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1553713980; hg19: chr2-179484475;