rs104894312

Positions:

• chr11-1841468-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal arthrogryposis type 2B1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Mar 23, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
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, 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	Genetic Services Laboratory, University of Chicago	Nov 25, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 07, 2022	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 09, 2018	- -
not provided, no classification provided	literature only	TNNI2 homepage - Leiden Muscular Dystrophy pages	-	- -
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) -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	55
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.76
GERP RS		2.8

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

LitVar

Other links and lift over

dbSNP: rs104894312; hg19: chr11-1862698; COSMIC: COSV99425559; COSMIC: COSV99425559;