rs778576436

Variant names:

• chr2-178630300-G-A
• rs778576436
• NM_001267550.2:c.44222C>T

Variant summary

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

The NM_001267550.2(TTN):​c.44222C>T​(p.Thr14741Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,460,922 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T14741T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 9.94
• 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-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=0.41102475).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.44222C>T	p.Thr14741Met	missense	Exon 239 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.39299C>T	p.Thr13100Met	missense	Exon 189 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.36518C>T	p.Thr12173Met	missense	Exon 188 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.44222C>T	p.Thr14741Met	missense	Exon 239 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.44066C>T	p.Thr14689Met	missense	Exon 237 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.43946C>T	p.Thr14649Met	missense	Exon 237 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248476 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1460922 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 726752

African (AFR) AF: 0.000180 AC: 6 AN: 33426

American (AMR) AF: 0.0000224 AC: 1 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111442

Other (OTH) AF: 0.0000331 AC: 2 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000762 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.52		Loss of catalytic residue at T13100 (P = 0.0841)
MVP		0.29
MPC		0.25
ClinPred		0.27	T
GERP RS		6.0
Mutation Taster		=66/34	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: rs778576436; hg19: chr2-179495027; COSMIC: COSV60180785; COSMIC: COSV60180785;