NM_001267550.2:c.51482C>T

Variant names:

• chr2-178609941-G-A
• rs16866412
• NM_001267550.2:c.51482C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.51482C>T​(p.Ala17161Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,612,702 control chromosomes in the GnomAD database, including 980 homozygotes. In-silico tool predicts 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. A17161T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.038 (193 hom., cov: 33)
  • Exomes 𝑓: 0.021 (787 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 7.95
• Publications: 25 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=0.0016416609).
• BP6: Variant 2-178609941-G-A is Benign according to our data. Variant chr2-178609941-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

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.51482C>T	p.Ala17161Val	missense	Exon 272 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.46559C>T	p.Ala15520Val	missense	Exon 222 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.43778C>T	p.Ala14593Val	missense	Exon 221 of 312	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.51482C>T	p.Ala17161Val	missense	Exon 272 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.51326C>T	p.Ala17109Val	missense	Exon 270 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.51206C>T	p.Ala17069Val	missense	Exon 270 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5822 AN: 151854 Hom.: 191 Cov.: 33

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.0545

Gnomad FIN AF: 0.0423

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0341 AC: 8452 AN: 247944 AF XY: 0.0346

Gnomad AFR exome AF: 0.0733

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.0408

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0210 AC: 30615 AN: 1460730 Hom.: 787 Cov.: 32 AF XY: 0.0221 AC XY: 16024 AN XY: 726660

African (AFR) AF: 0.0731 AC: 2443 AN: 33410

American (AMR) AF: 0.0152 AC: 678 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 663 AN: 26104

East Asian (EAS) AF: 0.136 AC: 5374 AN: 39616

South Asian (SAS) AF: 0.0577 AC: 4974 AN: 86200

European-Finnish (FIN) AF: 0.0404 AC: 2156 AN: 53348

Middle Eastern (MID) AF: 0.0400 AC: 230 AN: 5750

European-Non Finnish (NFE) AF: 0.0110 AC: 12278 AN: 1111292

Other (OTH) AF: 0.0302 AC: 1819 AN: 60314

GnomAD4 genome AF: 0.0384 AC: 5835 AN: 151972 Hom.: 193 Cov.: 33 AF XY: 0.0406 AC XY: 3013 AN XY: 74266

African (AFR) AF: 0.0736 AC: 3054 AN: 41496

American (AMR) AF: 0.0284 AC: 433 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3470

East Asian (EAS) AF: 0.133 AC: 678 AN: 5112

South Asian (SAS) AF: 0.0542 AC: 261 AN: 4818

European-Finnish (FIN) AF: 0.0423 AC: 448 AN: 10596

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 776 AN: 67918

Other (OTH) AF: 0.0393 AC: 83 AN: 2112

Alfa AF: 0.0231 Hom.: 272

Bravo AF: 0.0384

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.0676 AC: 254

ESP6500EA AF: 0.0131 AC: 108

ExAC AF: 0.0346 AC: 4185

Asia WGS AF: 0.0870 AC: 303 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0154

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	not provided (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	0.22
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.30
Sift	Benign	0.033	D
Polyphen		0.98	D
Vest4		0.24
MPC		0.25
ClinPred		0.028	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs16866412; hg19: chr2-179474668; COSMIC: COSV59894879; COSMIC: COSV59894879;