rs141856116

Variant names:

• chr2-178715208-C-T
• rs141856116
• NM_001267550.2:c.25978G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.25978G>A​(p.Val8660Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,644 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. V8660V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (8 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:24
• Conservation: PhyloP100: 3.09
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039693415).
• BP6: Variant 2-178715208-C-T is Benign according to our data. Variant chr2-178715208-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46771.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00346 (527/152252) while in subpopulation AFR AF = 0.0107 (444/41552). AF 95% confidence interval is 0.00986. There are 1 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

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.25978G>A	p.Val8660Ile	missense	Exon 90 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.25027G>A	p.Val8343Ile	missense	Exon 88 of 313	NP_001243779.1
	TTN	NM_133378.4		c.22246G>A	p.Val7416Ile	missense	Exon 87 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.25978G>A	p.Val8660Ile	missense	Exon 90 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.25978G>A	p.Val8660Ile	missense	Exon 90 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.25702G>A	p.Val8568Ile	missense	Exon 88 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152134 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00133 AC: 331 AN: 248738 AF XY: 0.00107

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.000995

GnomAD4 exome AF: 0.000777 AC: 1135 AN: 1461392 Hom.: 8 Cov.: 33 AF XY: 0.000732 AC XY: 532 AN XY: 726980

African (AFR) AF: 0.0109 AC: 366 AN: 33448

American (AMR) AF: 0.00143 AC: 64 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00689 AC: 180 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5754

European-Non Finnish (NFE) AF: 0.000363 AC: 403 AN: 1111666

Other (OTH) AF: 0.00177 AC: 107 AN: 60366

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152252 Hom.: 1 Cov.: 33 AF XY: 0.00329 AC XY: 245 AN XY: 74424

African (AFR) AF: 0.0107 AC: 444 AN: 41552

American (AMR) AF: 0.00216 AC: 33 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00408

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00963 AC: 36

ESP6500EA AF: 0.000609 AC: 5

ExAC AF: 0.00139 AC: 168

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000534

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	4	not provided (4)
-	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	Cardiovascular phenotype (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)
-	-	1	Ventricular tachycardia;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.95
Eigen	Benign	-0.077
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.98	T
PhyloP100		3.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.061
Sift	Benign	0.30	T
Polyphen		0.0020	B
Vest4		0.078
MVP		0.30
MPC		0.070
ClinPred		0.012	T
GERP RS		3.8
Mutation Taster		=81/19	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: rs141856116; hg19: chr2-179579935;