rs200103997

Variant names:

• chr2-178718054-C-T
• rs200103997
• NM_001267550.2:c.24952G>A

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.24952G>A​(p.Val8318Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V8318V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:14
• Conservation: PhyloP100: -0.0820
• Publications: 5 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006938517).
• BP6: Variant 2-178718054-C-T is Benign according to our data. Variant chr2-178718054-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166152.

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.24952G>A	p.Val8318Ile	missense	Exon 86 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.24001G>A	p.Val8001Ile	missense	Exon 84 of 313	NP_001243779.1
	TTN	NM_133378.4		c.21220G>A	p.Val7074Ile	missense	Exon 83 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.24952G>A	p.Val8318Ile	missense	Exon 86 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.24952G>A	p.Val8318Ile	missense	Exon 86 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.24676G>A	p.Val8226Ile	missense	Exon 84 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000587 AC: 146 AN: 248762 AF XY: 0.000615

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000770 AC: 1125 AN: 1461474 Hom.: 0 Cov.: 35 AF XY: 0.000752 AC XY: 547 AN XY: 727034

African (AFR) AF: 0.000149 AC: 5 AN: 33458

American (AMR) AF: 0.000157 AC: 7 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000962 AC: 1070 AN: 1111706

Other (OTH) AF: 0.000480 AC: 29 AN: 60364

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74442

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 67994

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000762 Hom.: 2

Bravo AF: 0.000578

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.000847 AC: 7

ExAC AF: 0.000736 AC: 89

EpiCase AF: 0.000764

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	5	not provided (8)
-	1	4	not specified (5)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.3
DANN	Benign	0.76
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.082
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.063
Sift	Benign	0.57	T
Polyphen		0.0080	B
Vest4		0.081
MVP		0.13
MPC		0.069
ClinPred		0.0012	T
GERP RS		1.1
Mutation Taster		=92/8	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: rs200103997; hg19: chr2-179582781; COSMIC: COSV100612863; COSMIC: COSV100612863;