rs762149243

Variant names:

• chr2-178662539-C-T
• rs762149243
• NM_001267550.2:c.36952G>A
• TTN p.Val12318Ile

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.36952G>A​(p.Val12318Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/14 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 0.017 (73 hom., cov: 9)
  • Exomes 𝑓: 0.0023 (145 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.95
• Publications: 1 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030481815).
• BP6: Variant 2-178662539-C-T is Benign according to our data. Variant chr2-178662539-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238757.

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.36952G>A	p.Val12318Ile	missense	Exon 176 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34354+427G>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31573+427G>A		intron	N/A	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.36952G>A	p.Val12318Ile	missense	Exon 176 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36952G>A	p.Val12318Ile	missense	Exon 176 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36676G>A	p.Val12226Ile	missense	Exon 174 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 1204 AN: 69592 Hom.: 72 Cov.: 9

Gnomad AFR AF: 0.0750

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00626

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.00854

GnomAD2 exomes AF: 0.00984 AC: 432 AN: 43918 AF XY: 0.00749

Gnomad AFR exome AF: 0.0927

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000277

Gnomad OTH exome AF: 0.00252

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00235 AC: 2272 AN: 967422 Hom.: 145 Cov.: 13 AF XY: 0.00206 AC XY: 993 AN XY: 483146

African (AFR) AF: 0.0918 AC: 1849 AN: 20138

American (AMR) AF: 0.00448 AC: 93 AN: 20744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18840

East Asian (EAS) AF: 0.00 AC: 0 AN: 30930

South Asian (SAS) AF: 0.000359 AC: 19 AN: 52868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31282

Middle Eastern (MID) AF: 0.00137 AC: 4 AN: 2930

European-Non Finnish (NFE) AF: 0.0000722 AC: 54 AN: 747478

Other (OTH) AF: 0.00599 AC: 253 AN: 42212

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0174 AC: 1212 AN: 69626 Hom.: 73 Cov.: 9 AF XY: 0.0160 AC XY: 508 AN XY: 31668

African (AFR) AF: 0.0752 AC: 1160 AN: 15420

American (AMR) AF: 0.00626 AC: 34 AN: 5430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2022

East Asian (EAS) AF: 0.00 AC: 0 AN: 1622

South Asian (SAS) AF: 0.00 AC: 0 AN: 1296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.000283 AC: 11 AN: 38876

Other (OTH) AF: 0.00843 AC: 7 AN: 830

Alfa AF: 0.0255 Hom.: 15

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	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
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.70
DANN	Benign	0.74
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.0
Mutation Taster		=98/2	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs762149243;

hg19: chr2-179527266;