rs568086259

Variant names:

• chr2-178658278-C-T
• rs568086259
• NM_001267550.2:c.37705G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001267550.2(TTN):​c.37705G>A​(p.Val12569Ile) 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V12569V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.033 (132 hom., cov: 10)
  • Exomes 𝑓: 0.0047 (231 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.143
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004136145).
• BP6: Variant 2-178658278-C-T is Benign according to our data. Variant chr2-178658278-C-T is described in ClinVar as Benign. ClinVar VariationId is 238760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.37705G>A	p.Val12569Ile	missense	Exon 185 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34522+727G>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31741+727G>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.37705G>A	p.Val12569Ile	missense	Exon 185 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37705G>A	p.Val12569Ile	missense	Exon 185 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.37429G>A	p.Val12477Ile	missense	Exon 183 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 2569 AN: 79136 Hom.: 123 Cov.: 10

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.000432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000549

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0135

Gnomad NFE AF: 0.000516

Gnomad OTH AF: 0.0305

GnomAD2 exomes AF: 0.0174 AC: 872 AN: 50002 AF XY: 0.0146

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.00961

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000609

Gnomad OTH exome AF: 0.00673

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00472 AC: 3814 AN: 807342 Hom.: 231 Cov.: 11 AF XY: 0.00423 AC XY: 1742 AN XY: 411764

African (AFR) AF: 0.164 AC: 2840 AN: 17294

American (AMR) AF: 0.0101 AC: 209 AN: 20720

Ashkenazi Jewish (ASJ) AF: 0.00106 AC: 19 AN: 17986

East Asian (EAS) AF: 0.00 AC: 0 AN: 33646

South Asian (SAS) AF: 0.000514 AC: 28 AN: 54518

European-Finnish (FIN) AF: 0.0000320 AC: 1 AN: 31260

Middle Eastern (MID) AF: 0.00620 AC: 17 AN: 2744

European-Non Finnish (NFE) AF: 0.000391 AC: 231 AN: 591252

Other (OTH) AF: 0.0124 AC: 469 AN: 37922

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0328 AC: 2601 AN: 79236 Hom.: 132 Cov.: 10 AF XY: 0.0331 AC XY: 1216 AN XY: 36750

African (AFR) AF: 0.143 AC: 2468 AN: 17282

American (AMR) AF: 0.0132 AC: 78 AN: 5906

Ashkenazi Jewish (ASJ) AF: 0.000432 AC: 1 AN: 2314

East Asian (EAS) AF: 0.00 AC: 0 AN: 3072

South Asian (SAS) AF: 0.000546 AC: 1 AN: 1832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4650

Middle Eastern (MID) AF: 0.0143 AC: 3 AN: 210

European-Non Finnish (NFE) AF: 0.000516 AC: 22 AN: 42616

Other (OTH) AF: 0.0296 AC: 28 AN: 946

Alfa AF: 0.0327 Hom.: 35

ExAC AF: 0.00384 AC: 89

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not specified (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.0
DANN	Benign	0.77
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.14
Vest4		0.12
MPC		0.076
ClinPred		0.0025	T
GERP RS		3.2
Mutation Taster		=92/8	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

Other links and lift over

dbSNP: rs568086259; hg19: chr2-179523005;