11-1841527-G-T

Variant names:

• chr11-1841527-G-T
• rs797046046
• NM_003282.4:c.525G>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_003282.4(TNNI2):​c.525G>T​(p.Lys175Asn) variant causes a missense change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNI2 NM_003282.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.11

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 14 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 11-1841527-G-T is Pathogenic according to our data. Variant chr11-1841527-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1841527-G-T is described in Lovd as [Likely_pathogenic]. Variant chr11-1841527-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.525G>T	p.Lys175Asn	missense_variant	Exon 8 of 8	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.525G>T	p.Lys175Asn	missense_variant	Exon 8 of 8		NP_001139301.1
TNNI2	NM_001145841.2	c.525G>T	p.Lys175Asn	missense_variant	Exon 6 of 6		NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.525G>T	p.Lys175Asn	missense_variant	Exon 8 of 8	2	NM_003282.4	ENSP00000371336.1
TNNI2	ENST00000252898.11	c.525G>T	p.Lys175Asn	missense_variant	Exon 7 of 7	3		ENSP00000252898.7
TNNI2	ENST00000381905.3	c.525G>T	p.Lys175Asn	missense_variant	Exon 6 of 6	3		ENSP00000371330.3
TNNI2	ENST00000381906.5	c.525G>T	p.Lys175Asn	missense_variant	Exon 8 of 8	3		ENSP00000371331.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal arthrogryposis type 2B1 Pathogenic:3

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with distal arthrogryposis type 2B1 (DA2B; MIM#601680) (PMIDs: 17194691, 25340332). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 27790376). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, an inframe-deletion of the same residue, p.(Lys175del) also known as p.(Lys176del), has been reported in individuals with DA2B (PMID: 26526134), demonstrating the importance of this amino acid for protein function. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in 3 unrelated individuals with DA2B (PMID: 23401156, ClinVar, LOVD). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 22, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25340332). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000212411 /PMID: 23401156). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;.;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.2	D;D;.;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.89
MutPred		0.40		Loss of ubiquitination at K175 (P = 0.0067);Loss of ubiquitination at K175 (P = 0.0067);Loss of ubiquitination at K175 (P = 0.0067);Loss of ubiquitination at K175 (P = 0.0067);Loss of ubiquitination at K175 (P = 0.0067);
MVP		1.0
MPC		0.95
ClinPred		1.0	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.68

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: rs797046046; hg19: chr11-1862757;