rs548471822

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001267550.2(TTN):c.25637A>G(p.Gln8546Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000435 in 1,609,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense, splice_region

Scores

Splicing: ADA: 0.003104

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.95

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016698748).

BP6

Variant 2-178717097-T-C is Benign according to our data. Variant chr2-178717097-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203338.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.25637A>G	p.Gln8546Arg	missense_variant, splice_region_variant	Exon 88 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.25637A>G	p.Gln8546Arg	missense_variant, splice_region_variant	Exon 88 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

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:

0.000142

AC:

AN:

247040

AF XY:

0.000149

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1457538

Hom.:

Cov.:

AF XY:

0.0000373

AC XY:

AN XY:

724424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33350

American (AMR)

AF:

0.00

AC:

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.000733

AC:

AN:

39588

South Asian (SAS)

AF:

0.00

AC:

AN:

85928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1108882

Other (OTH)

AF:

0.0000498

AC:

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.0000788

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000438

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 17, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Oct 18, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.21905A>G (p.Gln7302Arg) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 247040 control chromosomes, predominantly at a frequency of 0.0019 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.21905A>G has been reported in the literature in the index individual of a family affected with cardiac conduction disease. A different variant in LMNA gene (c.686T>C, I229T) was shown to co-segregate with disease in affected family members (Gao_2020). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.3624delC, p.Lys1209SerfsX28; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.030

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.73

T;T;.;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.017

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.9

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.0

N;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.28

T;.;.;.

Polyphen

0.0010

.;.;B;B

Vest4

0.28

MutPred

0.37

.;.;Gain of MoRF binding (P = 0.0857);Gain of MoRF binding (P = 0.0857);

MVP

0.10

MPC

0.090

ClinPred

0.065

GERP RS

5.4

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0031

dbscSNV1_RF

Benign

0.048

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over