rs199474801

Positions:

• chr11-1841523-GGAA-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_003282.4(TNNI2):​c.527_529del​(p.Lys176del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNI2 NM_003282.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 5.48

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 13 ACMG points.

• PM1: In a chain Troponin I, fast skeletal muscle (size 180) in uniprot entity TNNI2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003282.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003282.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-1841523-GGAA-G is Pathogenic according to our data. Variant chr11-1841523-GGAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1841523-GGAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.527_529del	p.Lys176del	inframe_deletion	8/8	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.527_529del	p.Lys176del	inframe_deletion	8/8		NP_001139301.1
TNNI2	NM_001145841.2	c.527_529del	p.Lys176del	inframe_deletion	6/6		NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.527_529del	p.Lys176del	inframe_deletion	8/8	2	NM_003282.4	ENSP00000371336	A1
TNNI2	ENST00000252898.11	c.527_529del	p.Lys176del	inframe_deletion	7/7	3		ENSP00000252898	A1
TNNI2	ENST00000381905.3	c.527_529del	p.Lys176del	inframe_deletion	6/6	3		ENSP00000371330	P4
TNNI2	ENST00000381906.5	c.527_529del	p.Lys176del	inframe_deletion	8/8	3		ENSP00000371331	A1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal arthrogryposis type 2B1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	-	We found this variant in a died fetus with multiple anomalies. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2006	- -

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 16924011, 16802141, 19325803, 25340332, 17380469, 27535533, 18331830, 23401156) -
not provided, no classification provided	literature only	TNNI2 homepage - Leiden Muscular Dystrophy pages	-	- -

TNNI2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 27, 2024

The TNNI2 c.527_529delAGA variant is predicted to result in an in-frame deletion (p.Lys176del). This variant was reported to segregate in five family members with distal arthrogryposis (Kimber et al. 2006. PubMed ID: 16924011). This variant has also been reported in several other unrelated individuals with distal arthrogryposis (Jiang et al. 2006. PubMed ID: 16802141; Beck et al. 2013. PubMed ID: 23401156). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs199474801; hg19: chr11-1862753;