NM_003282.4:c.83C>A

Variant names:

• chr11-1840553-C-A
• rs376294428
• NM_003282.4:c.83C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003282.4(TNNI2):​c.83C>A​(p.Thr28Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T28M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNNI2 NM_003282.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 0 publications found

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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.61809 (below the threshold of 3.09). Trascript score misZ: 1.172 (below the threshold of 3.09). GenCC associations: The gene is linked to distal arthrogryposis type 2B1, digitotalar dysmorphism, Sheldon-hall syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2560109).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI2	NM_003282.4	MANE Select	c.83C>A	p.Thr28Lys	missense	Exon 5 of 8	NP_003273.1	P48788-1
	TNNI2	NM_001145829.2		c.83C>A	p.Thr28Lys	missense	Exon 5 of 8	NP_001139301.1	P48788-1
	TNNI2	NM_001145841.2		c.83C>A	p.Thr28Lys	missense	Exon 3 of 6	NP_001139313.1	P48788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI2	ENST00000381911.6	TSL:2 MANE Select	c.83C>A	p.Thr28Lys	missense	Exon 5 of 8	ENSP00000371336.1	P48788-1
	TNNI2	ENST00000252898.11	TSL:3	c.83C>A	p.Thr28Lys	missense	Exon 4 of 7	ENSP00000252898.7	P48788-1
	TNNI2	ENST00000381905.3	TSL:3	c.83C>A	p.Thr28Lys	missense	Exon 3 of 6	ENSP00000371330.3	P48788-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460078 Hom.: 0 Cov.: 54 AF XY: 0.00 AC XY: 0 AN XY: 726308

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111728

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.76
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.11
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.23
Sift	Benign	0.29	T
Sift4G	Benign	0.25	T
Polyphen		0.075	B
Vest4		0.20
MutPred		0.41		Gain of ubiquitination at T28 (P = 0.0075)
MVP		0.94
MPC		0.36
ClinPred		0.088	T
GERP RS		1.8
PromoterAI		-0.0019	Neutral
Varity_R		0.058
gMVP		0.25
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs376294428; hg19: chr11-1861783;