rs144531477

Variant names:

• chr2-178795101-C-G
• rs144531477
• NM_001267550.2:c.1066G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178795101-C-G
• chr2-178795101-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):​c.1066G>C​(p.Glu356Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E356K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:3 O:1
• Conservation: PhyloP100: 6.43
• Publications: 4 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1G

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• early-onset myopathy with fatal cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• TTN-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopathy, myofibrillar, 9, with early respiratory failure

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tibial muscular dystrophy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2J

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary skeletal muscle disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1143195).

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.1066G>C	p.Glu356Gln	missense	Exon 7 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.1066G>C	p.Glu356Gln	missense	Exon 7 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.1066G>C	p.Glu356Gln	missense	Exon 7 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.1066G>C	p.Glu356Gln	missense	Exon 7 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.1066G>C	p.Glu356Gln	missense	Exon 7 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.1066G>C	p.Glu356Gln	missense	Exon 7 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251140 AF XY: 0.000177

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.000133 AC XY: 97 AN XY: 727182

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000148 AC: 165 AN: 1111986

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74356

African (AFR) AF: 0.0000482 AC: 2 AN: 41462

American (AMR) AF: 0.000589 AC: 9 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000722 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (4)
-	2	1	not specified (3)
-	1	-	Arthrogryposis syndrome (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.19	T
PhyloP100		6.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.18
Sift	Benign	0.18	T
Sift4G	Uncertain	0.055	T
Polyphen		0.96	D
Vest4		0.21
MVP		0.33
MPC		0.26
ClinPred		0.037	T
GERP RS		6.1
PromoterAI		-0.0046	Neutral
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144531477; hg19: chr2-179659828;