rs104894312
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003282.4(TNNI2):c.466C>T(p.Arg156*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
TNNI2
NM_003282.4 stop_gained
NM_003282.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.73
Genes affected
TNNI2 (HGNC:11946): (troponin I2, fast skeletal type) This gene encodes a fast-twitch skeletal muscle protein, a member of the troponin I gene family, and a component of the troponin complex including troponin T, troponin C and troponin I subunits. The troponin complex, along with tropomyosin, is responsible for the calcium-dependent regulation of striated muscle contraction. Mouse studies show that this component is also present in vascular smooth muscle and may play a role in regulation of smooth muscle function. In addition to muscle tissues, this protein is found in corneal epithelium, cartilage where it is an inhibitor of angiogenesis to inhibit tumor growth and metastasis, and mammary gland where it functions as a co-activator of estrogen receptor-related receptor alpha. This protein also suppresses tumor growth in human ovarian carcinoma. Mutations in this gene cause myopathy and distal arthrogryposis type 2B. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-1841468-C-T is Pathogenic according to our data. Variant chr11-1841468-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1841468-C-T is described in Lovd as [Pathogenic]. Variant chr11-1841468-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNNI2 | NM_003282.4 | c.466C>T | p.Arg156* | stop_gained | 8/8 | ENST00000381911.6 | NP_003273.1 | |
TNNI2 | NM_001145829.2 | c.466C>T | p.Arg156* | stop_gained | 8/8 | NP_001139301.1 | ||
TNNI2 | NM_001145841.2 | c.466C>T | p.Arg156* | stop_gained | 6/6 | NP_001139313.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TNNI2 | ENST00000381911.6 | c.466C>T | p.Arg156* | stop_gained | 8/8 | 2 | NM_003282.4 | ENSP00000371336.1 | ||
TNNI2 | ENST00000252898.11 | c.466C>T | p.Arg156* | stop_gained | 7/7 | 3 | ENSP00000252898.7 | |||
TNNI2 | ENST00000381905.3 | c.466C>T | p.Arg156* | stop_gained | 6/6 | 3 | ENSP00000371330.3 | |||
TNNI2 | ENST00000381906.5 | c.466C>T | p.Arg156* | stop_gained | 8/8 | 3 | ENSP00000371331.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Distal arthrogryposis type 2B1 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 06, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic in multiple patients with type 2B distal arthrogryposis [PMID 12592607, 17101001, 17194691, ClinVar ID: 12436] - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 25, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Sep 08, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 07, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust | Mar 23, 2023 | - - |
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Apr 09, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2022 | Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18331830, 21402185, 17101001, 25340332, 16497570, 16802141, 23401156, 12592607, 17194691, 33726816, 33060286) - |
not provided, no classification provided | literature only | TNNI2 homepage - Leiden Muscular Dystrophy pages | - | - - |
Ulnar deviation of the wrist;C0265213:Distal arthrogryposis;C1393871:Congenital finger flexion contractures;C1860450:Calcaneovalgus deformity Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 06, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at