rs16866380

Variant names:

• chr2-178530833-G-A
• rs16866380
• NM_001267550.2:c.105782C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178530833-G-A
• chr2-178530833-G-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.105782C>T​(p.Pro35261Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0299 in 1,613,654 control chromosomes in the GnomAD database, including 1,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. P35261T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (227 hom., cov: 32)
  • Exomes 𝑓: 0.029 (1282 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 5.59
• Publications: 18 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=0.0016560853).
• BP6: Variant 2-178530833-G-A is Benign according to our data. Variant chr2-178530833-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 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.105782C>T	p.Pro35261Leu	missense	Exon 358 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.100859C>T	p.Pro33620Leu	missense	Exon 308 of 313	NP_001243779.1
	TTN	NM_133378.4		c.98078C>T	p.Pro32693Leu	missense	Exon 307 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.105782C>T	p.Pro35261Leu	missense	Exon 358 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.105626C>T	p.Pro35209Leu	missense	Exon 356 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.105506C>T	p.Pro35169Leu	missense	Exon 356 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0424 AC: 6436 AN: 151856 Hom.: 227 Cov.: 32

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0463

Gnomad FIN AF: 0.00237

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0575

GnomAD2 exomes AF: 0.0401 AC: 9981 AN: 249042 AF XY: 0.0401

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.0317

Gnomad ASJ exome AF: 0.0417

Gnomad EAS exome AF: 0.176

Gnomad FIN exome AF: 0.00353

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0392

GnomAD4 exome AF: 0.0286 AC: 41792 AN: 1461680 Hom.: 1282 Cov.: 34 AF XY: 0.0290 AC XY: 21104 AN XY: 727124

African (AFR) AF: 0.0753 AC: 2521 AN: 33474

American (AMR) AF: 0.0337 AC: 1507 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 1112 AN: 26136

East Asian (EAS) AF: 0.179 AC: 7097 AN: 39694

South Asian (SAS) AF: 0.0490 AC: 4224 AN: 86256

European-Finnish (FIN) AF: 0.00333 AC: 178 AN: 53400

Middle Eastern (MID) AF: 0.0966 AC: 557 AN: 5768

European-Non Finnish (NFE) AF: 0.0201 AC: 22381 AN: 1111858

Other (OTH) AF: 0.0367 AC: 2215 AN: 60372

GnomAD4 genome AF: 0.0424 AC: 6448 AN: 151974 Hom.: 227 Cov.: 32 AF XY: 0.0423 AC XY: 3137 AN XY: 74244

African (AFR) AF: 0.0744 AC: 3081 AN: 41404

American (AMR) AF: 0.0399 AC: 610 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.164 AC: 847 AN: 5160

South Asian (SAS) AF: 0.0465 AC: 224 AN: 4814

European-Finnish (FIN) AF: 0.00237 AC: 25 AN: 10538

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0201 AC: 1367 AN: 68000

Other (OTH) AF: 0.0578 AC: 122 AN: 2110

Alfa AF: 0.0300 Hom.: 344

Bravo AF: 0.0468

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.0683 AC: 260

ESP6500EA AF: 0.0208 AC: 171

ExAC AF: 0.0401 AC: 4848

Asia WGS AF: 0.0950 AC: 330 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0289

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.90
Eigen	Benign	0.032
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		5.6
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Polyphen		0.38	B
Vest4		0.18
MPC		0.089
ClinPred		0.046	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs16866380; hg19: chr2-179395560; COSMIC: COSV107419466; COSMIC: COSV107419466;