rs371056974

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001267550.2(TTN):​c.919G>A​(p.Val307Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000266 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V307V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

4
5
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.73

Publications

5 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 Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • dilated cardiomyopathy 1G
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • early-onset myopathy with fatal cardiomyopathy
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
  • 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
  • tibial muscular dystrophy
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
  • autosomal recessive limb-girdle muscular dystrophy type 2J
    Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
  • hypertrophic cardiomyopathy 9
    Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
  • 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
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.23235577).
BP6
Variant 2-178795248-C-T is Benign according to our data. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122. Variant chr2-178795248-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 405122.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.919G>A p.Val307Met missense_variant Exon 7 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7
TTNNM_133379.5 linkc.919G>A p.Val307Met missense_variant Exon 7 of 46 ENST00000360870.10 NP_596870.2 Q8WZ42-6Q7Z3B7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.919G>A p.Val307Met missense_variant Exon 7 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7
TTNENST00000360870.10 linkc.919G>A p.Val307Met missense_variant Exon 7 of 46 5 NM_133379.5 ENSP00000354117.4 Q8WZ42-6

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
151996
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000478
AC:
12
AN:
250840
AF XY:
0.0000516
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000233
AC:
34
AN:
1461824
Hom.:
0
Cov.:
32
AF XY:
0.0000275
AC XY:
20
AN XY:
727216
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000894
AC:
4
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.000101
AC:
4
AN:
39698
South Asian (SAS)
AF:
0.0000812
AC:
7
AN:
86258
European-Finnish (FIN)
AF:
0.0000374
AC:
2
AN:
53408
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000117
AC:
13
AN:
1111964
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000592
AC:
9
AN:
152112
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74394
show subpopulations
African (AFR)
AF:
0.000145
AC:
6
AN:
41460
American (AMR)
AF:
0.000131
AC:
2
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.000208
AC:
1
AN:
4810
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Jan 21, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 04, 2023
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Sep 15, 2016
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
24
DANN
Benign
0.95
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;.;D;D;D;D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.23
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.071
D
PhyloP100
5.7
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.8
N;N;.;.;N;N;.;N
REVEL
Benign
0.26
Sift
Pathogenic
0.0
D;D;.;.;D;D;.;D
Sift4G
Uncertain
0.0020
.;.;.;.;.;.;.;D
Polyphen
1.0
.;.;.;D;.;.;D;D
Vest4
0.25
MVP
0.60
MPC
0.37
ClinPred
0.18
T
GERP RS
6.1
PromoterAI
0.015
Neutral
Mutation Taster
=71/29
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs371056974; hg19: chr2-179659975; API