rs16866406

Variant names:

• chr2-178592420-G-A
• rs16866406
• NM_001267550.2:c.59585C>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.59585C>T​(p.Pro19862Leu) variant causes a missense change. The variant allele was found at a frequency of 0.153 in 1,612,920 control chromosomes in the GnomAD database, including 22,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. P19862S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2002 hom., cov: 33)
  • Exomes 𝑓: 0.15 (20171 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 4.76
• Publications: 30 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=0.0036236942).
• BP6: Variant 2-178592420-G-A is Benign according to our data. Variant chr2-178592420-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.431 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.59585C>T	p.Pro19862Leu	missense	Exon 301 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.54662C>T	p.Pro18221Leu	missense	Exon 251 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.51881C>T	p.Pro17294Leu	missense	Exon 250 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.59585C>T	p.Pro19862Leu	missense	Exon 301 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.59429C>T	p.Pro19810Leu	missense	Exon 299 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.59309C>T	p.Pro19770Leu	missense	Exon 299 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21643 AN: 151938 Hom.: 1996 Cov.: 33

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.177 AC: 43914 AN: 248040 AF XY: 0.181

Gnomad AFR exome AF: 0.0705

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.155 AC: 225731 AN: 1460864 Hom.: 20171 Cov.: 36 AF XY: 0.158 AC XY: 114647 AN XY: 726692

African (AFR) AF: 0.0716 AC: 2393 AN: 33442

American (AMR) AF: 0.148 AC: 6592 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4541 AN: 26108

East Asian (EAS) AF: 0.435 AC: 17254 AN: 39636

South Asian (SAS) AF: 0.256 AC: 22064 AN: 86164

European-Finnish (FIN) AF: 0.151 AC: 8062 AN: 53376

Middle Eastern (MID) AF: 0.132 AC: 761 AN: 5758

European-Non Finnish (NFE) AF: 0.139 AC: 154197 AN: 1111354

Other (OTH) AF: 0.164 AC: 9867 AN: 60336

GnomAD4 genome AF: 0.142 AC: 21654 AN: 152056 Hom.: 2002 Cov.: 33 AF XY: 0.147 AC XY: 10955 AN XY: 74304

African (AFR) AF: 0.0754 AC: 3130 AN: 41502

American (AMR) AF: 0.129 AC: 1970 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 605 AN: 3470

East Asian (EAS) AF: 0.446 AC: 2289 AN: 5132

South Asian (SAS) AF: 0.264 AC: 1270 AN: 4812

European-Finnish (FIN) AF: 0.163 AC: 1729 AN: 10594

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9905 AN: 67962

Other (OTH) AF: 0.138 AC: 292 AN: 2112

Alfa AF: 0.147 Hom.: 5858

Bravo AF: 0.138

TwinsUK AF: 0.134 AC: 496

ALSPAC AF: 0.140 AC: 541

ESP6500AA AF: 0.0765 AC: 283

ESP6500EA AF: 0.147 AC: 1205

ExAC AF: 0.177 AC: 21337

Asia WGS AF: 0.341 AC: 1185 AN: 3476

EpiCase AF: 0.138

EpiControl AF: 0.141

ClinVar

ClinVar submissions

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	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	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.92
Eigen	Benign	0.055
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.19
Sift	Benign	0.17	T
Polyphen		0.0080	B
Vest4		0.18
MPC		0.092
ClinPred		0.019	T
GERP RS		5.2
Mutation Taster		=93/7	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: rs16866406; hg19: chr2-179457147; COSMIC: COSV59894787; COSMIC: COSV59894787;