11-1840553-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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 Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.2560109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.83C>A	p.Thr28Lys	missense_variant	Exon 5 of 8	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.83C>A	p.Thr28Lys	missense_variant	Exon 5 of 8		NP_001139301.1
TNNI2	NM_001145841.2	c.83C>A	p.Thr28Lys	missense_variant	Exon 3 of 6		NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.83C>A	p.Thr28Lys	missense_variant	Exon 5 of 8	2	NM_003282.4	ENSP00000371336.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.77	.;.;T;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.4	L;L;.;L;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.27	N;N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.29	T;T;.;T;T
Sift4G	Benign	0.25	T;T;T;T;T
Polyphen		0.075	B;B;.;B;.
Vest4		0.20
MutPred		0.41		Gain of ubiquitination at T28 (P = 0.0075);Gain of ubiquitination at T28 (P = 0.0075);Gain of ubiquitination at T28 (P = 0.0075);Gain of ubiquitination at T28 (P = 0.0075);Gain of ubiquitination at T28 (P = 0.0075);
MVP		0.94
MPC		0.36
ClinPred		0.088	T
GERP RS		1.8
Varity_R		0.058
gMVP		0.25

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-1861783;