rs56130023

Variant names:

• chr2-178583723-G-A
• rs56130023
• NM_001267550.2:c.65459C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.65459C>T​(p.Thr21820Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0006 in 1,612,364 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:13
• Conservation: PhyloP100: 5.48
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007015437).
• BP6: Variant 2-178583723-G-A is Benign according to our data. Variant chr2-178583723-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47222.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000581 (848/1460162) while in subpopulation MID AF = 0.00382 (22/5754). AF 95% confidence interval is 0.00259. There are 4 homozygotes in GnomAdExome4. There are 448 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.65459C>T	p.Thr21820Ile	missense	Exon 312 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.60536C>T	p.Thr20179Ile	missense	Exon 262 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.57755C>T	p.Thr19252Ile	missense	Exon 261 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.65459C>T	p.Thr21820Ile	missense	Exon 312 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.65303C>T	p.Thr21768Ile	missense	Exon 310 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.65183C>T	p.Thr21728Ile	missense	Exon 310 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152084 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00102 AC: 253 AN: 246992 AF XY: 0.000955

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000322

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.000581 AC: 848 AN: 1460162 Hom.: 4 Cov.: 31 AF XY: 0.000617 AC XY: 448 AN XY: 726306

African (AFR) AF: 0.00180 AC: 60 AN: 33424

American (AMR) AF: 0.000471 AC: 21 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 443 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5754

European-Non Finnish (NFE) AF: 0.000174 AC: 193 AN: 1111188

Other (OTH) AF: 0.00179 AC: 108 AN: 60270

GnomAD4 genome AF: 0.000782 AC: 119 AN: 152202 Hom.: 1 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74396

African (AFR) AF: 0.00101 AC: 42 AN: 41562

American (AMR) AF: 0.000262 AC: 4 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67990

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00110 Hom.: 4

Bravo AF: 0.00100

ESP6500AA AF: 0.000528 AC: 2

ESP6500EA AF: 0.000973 AC: 8

ExAC AF: 0.000820 AC: 99

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000775

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not specified (5)
-	1	3	not provided (4)
-	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	Cardiomyopathy (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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.89
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.30
Sift	Benign	0.11	T
Polyphen		0.13	B
Vest4		0.55
MVP		0.36
MPC		0.10
ClinPred		0.042	T
GERP RS		6.0
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs56130023; hg19: chr2-179448450;