rs16866457

Variant names:

• chr2-178714529-C-T
• rs16866457
• NM_001267550.2:c.26245G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.26245G>A​(p.Val8749Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,612,974 control chromosomes in the GnomAD database, including 91 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8749A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (42 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (49 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 0.0300
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004145384).
• BP6: Variant 2-178714529-C-T is Benign according to our data. Variant chr2-178714529-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1899/152160) while in subpopulation AFR AF = 0.0409 (1698/41526). AF 95% confidence interval is 0.0393. There are 42 homozygotes in GnomAd4. There are 875 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.26245G>A	p.Val8749Ile	missense	Exon 91 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.25294G>A	p.Val8432Ile	missense	Exon 89 of 313	NP_001243779.1
	TTN	NM_133378.4		c.22513G>A	p.Val7505Ile	missense	Exon 88 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.26245G>A	p.Val8749Ile	missense	Exon 91 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.26245G>A	p.Val8749Ile	missense	Exon 91 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.25969G>A	p.Val8657Ile	missense	Exon 89 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1899 AN: 152042 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00441 AC: 1093 AN: 247828 AF XY: 0.00361

Gnomad AFR exome AF: 0.0419

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.0311

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00203 AC: 2966 AN: 1460814 Hom.: 49 Cov.: 33 AF XY: 0.00189 AC XY: 1373 AN XY: 726662

African (AFR) AF: 0.0438 AC: 1466 AN: 33442

American (AMR) AF: 0.00226 AC: 101 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 806 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.000242 AC: 269 AN: 1111478

Other (OTH) AF: 0.00511 AC: 308 AN: 60330

GnomAD4 genome AF: 0.0125 AC: 1899 AN: 152160 Hom.: 42 Cov.: 33 AF XY: 0.0118 AC XY: 875 AN XY: 74372

African (AFR) AF: 0.0409 AC: 1698 AN: 41526

American (AMR) AF: 0.00360 AC: 55 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 67992

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00621 Hom.: 34

Bravo AF: 0.0146

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0348 AC: 129

ESP6500EA AF: 0.00134 AC: 11

ExAC AF: 0.00466 AC: 563

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000772

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.57
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.030
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.042
Sift	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.071
MVP		0.092
MPC		0.068
ClinPred		0.000050	T
GERP RS		3.0
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16866457; hg19: chr2-179579256; COSMIC: COSV99045525; COSMIC: COSV99045525;