rs199474800

Positions:

• chr11-1841497-CGAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_003282.4(TNNI2):​c.499_501delGAG​(p.Glu167del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.09

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 Likely_pathogenic. Variant got 7 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 11-1841497-CGAG-C is Pathogenic according to our data. Variant chr11-1841497-CGAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-1841497-CGAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.499_501delGAG	p.Glu167del	conservative_inframe_deletion	8/8	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.499_501delGAG	p.Glu167del	conservative_inframe_deletion	8/8		NP_001139301.1
TNNI2	NM_001145841.2	c.499_501delGAG	p.Glu167del	conservative_inframe_deletion	6/6		NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.499_501delGAG	p.Glu167del	conservative_inframe_deletion	8/8	2	NM_003282.4	ENSP00000371336.1
TNNI2	ENST00000252898.11	c.499_501delGAG	p.Glu167del	conservative_inframe_deletion	7/7	3		ENSP00000252898.7
TNNI2	ENST00000381905.3	c.499_501delGAG	p.Glu167del	conservative_inframe_deletion	6/6	3		ENSP00000371330.3
TNNI2	ENST00000381906.5	c.499_501delGAG	p.Glu167del	conservative_inframe_deletion	8/8	3		ENSP00000371331.1

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: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2022	In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18331830, 23401156, 35052370, 16497570, 33060286) -
not provided, no classification provided	literature only	TNNI2 homepage - Leiden Muscular Dystrophy pages	-	- -

Distal arthrogryposis type 2B1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2006

- -

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: rs199474800; hg19: chr11-1862727;