rs146590898

Variant names:

• chr2-178773224-A-C
• rs146590898
• NM_001267550.2:c.7740T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.7740T>G​(p.Ile2580Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,613,822 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. I2580T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (6 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.454
• Publications: 3 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=0.005093366).
• BP6: Variant 2-178773224-A-C is Benign according to our data. Variant chr2-178773224-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00348 (530/152222) while in subpopulation AFR AF = 0.0124 (516/41528). AF 95% confidence interval is 0.0115. There are 0 homozygotes in GnomAd4. There are 257 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.7740T>G	p.Ile2580Met	missense	Exon 33 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.7740T>G	p.Ile2580Met	missense	Exon 33 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.7740T>G	p.Ile2580Met	missense	Exon 33 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.7740T>G	p.Ile2580Met	missense	Exon 33 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.7740T>G	p.Ile2580Met	missense	Exon 33 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.7464T>G	p.Ile2488Met	missense	Exon 31 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000843 AC: 211 AN: 250172 AF XY: 0.000606

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000337 AC: 493 AN: 1461600 Hom.: 6 Cov.: 32 AF XY: 0.000274 AC XY: 199 AN XY: 727084

African (AFR) AF: 0.0128 AC: 430 AN: 33474

American (AMR) AF: 0.000470 AC: 21 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111926

Other (OTH) AF: 0.000596 AC: 36 AN: 60376

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74420

African (AFR) AF: 0.0124 AC: 516 AN: 41528

American (AMR) AF: 0.000458 AC: 7 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68010

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00118 Hom.: 5

Bravo AF: 0.00380

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00114 AC: 138

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	Cardiomyopathy (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	0.085
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.53
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.45
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.15	T
Sift4G	Benign	0.18	T
Polyphen		0.045	B
Vest4		0.29
MVP		0.20
MPC		0.090
ClinPred		0.0067	T
GERP RS		1.9
Mutation Taster		=99/1	polymorphism

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: rs146590898; hg19: chr2-179637951;