chr2-178709575-C-T

Variant names:

• chr2-178709575-C-T
• rs537805395
• NM_001267550.2:c.28744G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001267550.2(TTN):​c.28744G>A​(p.Val9582Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,452,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0380
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062463433).

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.28744G>A	p.Val9582Ile	missense	Exon 99 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.27793G>A	p.Val9265Ile	missense	Exon 97 of 313	NP_001243779.1
	TTN	NM_133378.4		c.25012G>A	p.Val8338Ile	missense	Exon 96 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.28744G>A	p.Val9582Ile	missense	Exon 99 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.28744G>A	p.Val9582Ile	missense	Exon 99 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.28468G>A	p.Val9490Ile	missense	Exon 97 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 247282 AF XY: 0.0000298

Gnomad AFR exome AF: 0.00

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: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1452072 Hom.: 0 Cov.: 31 AF XY: 0.0000222 AC XY: 16 AN XY: 720158

African (AFR) AF: 0.0000300 AC: 1 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1103938

Other (OTH) AF: 0.00 AC: 0 AN: 59946

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	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 (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.87
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.038
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.10
Sift	Benign	0.21	T
Polyphen		0.0090	B
Vest4		0.13
MutPred		0.41		Loss of catalytic residue at V9265 (P = 0.079)
MVP		0.16
MPC		0.069
ClinPred		0.088	T
GERP RS		4.1
Mutation Taster		=95/5	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: rs537805395; hg19: chr2-179574302; COSMIC: COSV59950661;