rs376548316

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_001267550.2(TTN):​c.2967C>A​(p.Phe989Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000861 in 1,614,046 control chromosomes in the GnomAD database, including 1 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000094 ( 1 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

5
6
6

Clinical Significance

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

Conservation

PhyloP100: 6.79
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.36528876).
BP6
Variant 2-178782939-G-T is Benign according to our data. Variant chr2-178782939-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 535063.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkc.2967C>A p.Phe989Leu missense_variant 18/363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7
TTNNM_133379.5 linkc.2967C>A p.Phe989Leu missense_variant 18/46 ENST00000360870.10 NP_596870.2 Q8WZ42-6Q7Z3B7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.2967C>A p.Phe989Leu missense_variant 18/3635 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7
TTNENST00000360870.10 linkc.2967C>A p.Phe989Leu missense_variant 18/465 NM_133379.5 ENSP00000354117.4 Q8WZ42-6

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000558
AC:
14
AN:
250792
Hom.:
0
AF XY:
0.0000517
AC XY:
7
AN XY:
135492
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000944
AC:
138
AN:
1461828
Hom.:
1
Cov.:
32
AF XY:
0.0000949
AC XY:
69
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000123
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000761
Hom.:
0
Bravo
AF:
0.00000378
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 15, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsMar 14, 2024Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 11, 2020This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Benign
-0.037
T
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
25
DANN
Uncertain
0.99
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;.;D;D;D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.37
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.30
T
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-4.1
D;D;.;.;D;D;.;D
REVEL
Uncertain
0.41
Sift
Benign
0.080
T;T;.;.;T;T;.;T
Sift4G
Uncertain
0.0030
.;.;.;.;.;.;.;D
Polyphen
1.0, 1.0
.;.;.;D;.;.;D;D
Vest4
0.50
MutPred
0.68
Gain of loop (P = 0.1069);.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP
0.57
MPC
0.50
ClinPred
0.34
T
GERP RS
6.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376548316; hg19: chr2-179647666; API