NM_003282.4:c.41G>T

Variant names:

• chr11-1840428-G-T
• NM_003282.4:c.41G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PP3_Moderate BS2

The NM_003282.4(TNNI2):​c.41G>T​(p.Arg14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,458,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TNNI2 NM_003282.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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 0 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.41G>T	p.Arg14Leu	missense_variant	Exon 4 of 8	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.41G>T	p.Arg14Leu	missense_variant	Exon 4 of 8		NP_001139301.1
TNNI2	NM_001145841.2	c.41G>T	p.Arg14Leu	missense_variant	Exon 2 of 6		NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.41G>T	p.Arg14Leu	missense_variant	Exon 4 of 8	2	NM_003282.4	ENSP00000371336.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458142 Hom.: 0 Cov.: 35 AF XY: 0.00000827 AC XY: 6 AN XY: 725352

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D;.;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.93	.;.;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;.;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;D;.;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.70
MutPred		0.60		Loss of methylation at K19 (P = 0.0354);Loss of methylation at K19 (P = 0.0354);Loss of methylation at K19 (P = 0.0354);Loss of methylation at K19 (P = 0.0354);Loss of methylation at K19 (P = 0.0354);
MVP		0.99
MPC		0.99
ClinPred		1.0	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-1861658;