rs104894312

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 3.73

Publications

9 publications found

Variant links:

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]

TNNI2 Gene-Disease associations (from GenCC):

distal arthrogryposis type 2B1
Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
digitotalar dysmorphism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Sheldon-hall syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TNNI2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 10 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 VariationId is 12436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI2	NM_003282.4 link	c.466C>T	p.Arg156*	stop_gained	Exon 8 of 8	ENST00000381911.6	NP_003273.1	P48788-1
TNNI2	NM_001145829.2 link	c.466C>T	p.Arg156*	stop_gained	Exon 8 of 8		NP_001139301.1	P48788-1
TNNI2	NM_001145841.2 link	c.466C>T	p.Arg156*	stop_gained	Exon 6 of 6		NP_001139313.1	P48788-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNNI2	ENST00000381911.6 link	c.466C>T	p.Arg156*	stop_gained	Exon 8 of 8	2	NM_003282.4	ENSP00000371336.1	P48788-1
TNNI2	ENST00000252898.11 link	c.466C>T	p.Arg156*	stop_gained	Exon 7 of 7	3		ENSP00000252898.7	P48788-1
TNNI2	ENST00000381905.3 link	c.466C>T	p.Arg156*	stop_gained	Exon 6 of 6	3		ENSP00000371330.3	P48788-2
TNNI2	ENST00000381906.5 link	c.466C>T	p.Arg156*	stop_gained	Exon 8 of 8	3		ENSP00000371331.1	P48788-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

Dec 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 07, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 06, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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] -

Nov 25, 2015

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 08, 2023

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 23, 2023

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2Other:1

TNNI2 homepage - Leiden Muscular Dystrophy pages

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 09, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Ulnar deviation of the wrist;C0265213:Distal arthrogryposis;C1393871:Congenital finger flexion contractures;C1860450:Calcaneovalgus deformity

Pathogenic:1

Mar 06, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.81

PhyloP100

3.7

Vest4

0.76

GERP RS

2.8

Mutation Taster

=1/199

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over