rs55675869

Variant names:

• chr2-178537013-C-T
• rs55675869
• NM_001267550.2:c.100096G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178537013-C-T
• chr2-178537013-C-A

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.100096G>A​(p.Val33366Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,613,222 control chromosomes in the GnomAD database, including 584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (61 hom., cov: 33)
  • Exomes 𝑓: 0.024 (523 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 7.91
• Publications: 19 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=0.0052649975).
• BP6: Variant 2-178537013-C-T is Benign according to our data. Variant chr2-178537013-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0586 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.100096G>A	p.Val33366Ile	missense	Exon 356 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.95173G>A	p.Val31725Ile	missense	Exon 306 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.92392G>A	p.Val30798Ile	missense	Exon 305 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.100096G>A	p.Val33366Ile	missense	Exon 356 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.99940G>A	p.Val33314Ile	missense	Exon 354 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.99820G>A	p.Val33274Ile	missense	Exon 354 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3286 AN: 152162 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0280 AC: 6928 AN: 247728 AF XY: 0.0266

Gnomad AFR exome AF: 0.00487

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.0664

Gnomad FIN exome AF: 0.0638

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0238 AC: 34797 AN: 1460942 Hom.: 523 Cov.: 32 AF XY: 0.0234 AC XY: 17007 AN XY: 726706

African (AFR) AF: 0.00407 AC: 136 AN: 33448

American (AMR) AF: 0.0318 AC: 1419 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 384 AN: 26120

East Asian (EAS) AF: 0.0639 AC: 2536 AN: 39658

South Asian (SAS) AF: 0.00722 AC: 622 AN: 86114

European-Finnish (FIN) AF: 0.0628 AC: 3348 AN: 53350

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5766

European-Non Finnish (NFE) AF: 0.0224 AC: 24934 AN: 1111516

Other (OTH) AF: 0.0225 AC: 1359 AN: 60340

GnomAD4 genome AF: 0.0216 AC: 3285 AN: 152280 Hom.: 61 Cov.: 33 AF XY: 0.0229 AC XY: 1705 AN XY: 74452

African (AFR) AF: 0.00448 AC: 186 AN: 41562

American (AMR) AF: 0.0216 AC: 331 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.0642 AC: 332 AN: 5168

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4826

European-Finnish (FIN) AF: 0.0617 AC: 655 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1601 AN: 68022

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0233 Hom.: 177

Bravo AF: 0.0190

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00522 AC: 20

ESP6500EA AF: 0.0207 AC: 171

ExAC AF: 0.0276 AC: 3329

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0219

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.89
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.31
Sift	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.27
MPC		0.42
ClinPred		0.029	T
GERP RS		5.5
Mutation Taster		=97/3	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: rs55675869; hg19: chr2-179401740; COSMIC: COSV60084979; COSMIC: COSV60084979;