2-178599220-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000589042.5(TTN):c.56573G>A(p.Arg18858Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000693 in 1,528,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

TTN
ENST00000589042.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.12

Publications

2 publications found

Variant links:

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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.56573G>A	p.Arg18858Gln	missense	Exon 290 of 363	NP_001254479.2
TTN	NM_001256850.1		c.51650G>A	p.Arg17217Gln	missense	Exon 240 of 313	NP_001243779.1
TTN	NM_133378.4		c.48869G>A	p.Arg16290Gln	missense	Exon 239 of 312	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.56573G>A	p.Arg18858Gln	missense	Exon 290 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.56417G>A	p.Arg18806Gln	missense	Exon 288 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.56297G>A	p.Arg18766Gln	missense	Exon 288 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000542

AC:

AN:

184522

AF XY:

0.0000305

show subpopulations

Gnomad AFR exome

AF:

0.0000696

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000741

AC:

102

AN:

1376898

Hom.:

Cov.:

AF XY:

0.0000739

AC XY:

AN XY:

676834

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30464

American (AMR)

AF:

0.0000326

AC:

AN:

30696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21014

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38550

South Asian (SAS)

AF:

0.000146

AC:

AN:

68408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5376

European-Non Finnish (NFE)

AF:

0.0000809

AC:

AN:

1074940

Other (OTH)

AF:

0.0000352

AC:

AN:

56782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000567

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000829

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.3

PhyloP100

6.1

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.41

Sift

Uncertain

0.0060

Polyphen

0.93

Vest4

0.43

MutPred

0.75

Loss of MoRF binding (P = 0.2867)

MVP

0.37

MPC

0.30

ClinPred

0.36

GERP RS

5.1

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over