rs104894311

chr11-1841523-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003282.4(TNNI2):c.521G>A(p.Arg174Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R174W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNI2 NM_003282.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.23

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 16 ACMG points.

• PM1: In a chain Troponin I, fast skeletal muscle (size 180) in uniprot entity TNNI2_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_003282.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-1841522-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333897.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 11-1841523-G-A is Pathogenic according to our data. Variant chr11-1841523-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1841523-G-A is described in UniProt as null. Variant chr11-1841523-G-A is described in UniProt as null. Variant chr11-1841523-G-A is described in UniProt as null. Variant chr11-1841523-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-1841523-G-A is described in Lovd as [Pathogenic]. Variant chr11-1841523-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI2	NM_003282.4	c.521G>A	p.Arg174Gln	missense_variant	8/8	ENST00000381911.6
TNNI2	NM_001145829.2	c.521G>A	p.Arg174Gln	missense_variant	8/8
TNNI2	NM_001145841.2	c.521G>A	p.Arg174Gln	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI2	ENST00000381911.6	c.521G>A	p.Arg174Gln	missense_variant	8/8	2	NM_003282.4	A1
TNNI2	ENST00000252898.11	c.521G>A	p.Arg174Gln	missense_variant	7/7	3		A1
TNNI2	ENST00000381905.3	c.521G>A	p.Arg174Gln	missense_variant	6/6	3		P4
TNNI2	ENST00000381906.5	c.521G>A	p.Arg174Gln	missense_variant	8/8	3		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal arthrogryposis type 2B1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID: 23401156, 12592607, ClinVar ID: 12435] -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jan 23, 2019	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate a damaging effect as R174Q results in increased calcium sensitivity (Robinson et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 12592607, 17194691, 23850728, 23401156, 30630514) -
not provided, no classification provided	literature only	TNNI2 homepage - Leiden Muscular Dystrophy pages	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;D;.;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D;D;.;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.92
MutPred		0.68		Loss of MoRF binding (P = 0.0309);Loss of MoRF binding (P = 0.0309);Loss of MoRF binding (P = 0.0309);Loss of MoRF binding (P = 0.0309);Loss of MoRF binding (P = 0.0309);
MVP		0.99
MPC		0.93
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.66
gMVP		0.40

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: rs104894311; hg19: chr11-1862753;