11-1840530-T-C

Position:

• chr11-1840530-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003282.4(TNNI2):​c.60T>C​(p.Ser20Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,611,762 control chromosomes in the GnomAD database, including 613,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52802 hom., cov: 36)
  • Exomes 𝑓: 0.88 (560484 hom.)
• Consequence: TNNI2 NM_003282.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.300

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-1840530-T-C is Benign according to our data. Variant chr11-1840530-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1840530-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.60T>C	p.Ser20Ser	splice_region_variant, synonymous_variant	5/8	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.60T>C	p.Ser20Ser	splice_region_variant, synonymous_variant	5/8		NP_001139301.1
TNNI2	NM_001145841.2	c.60T>C	p.Ser20Ser	splice_region_variant, synonymous_variant	3/6		NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.60T>C	p.Ser20Ser	splice_region_variant, synonymous_variant	5/8	2	NM_003282.4	ENSP00000371336.1

Frequencies

GnomAD3 genomes AF: 0.827 AC: 125656 AN: 152026 Hom.: 52761 Cov.: 36

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.836

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.878

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.841

Gnomad NFE AF: 0.877

Gnomad OTH AF: 0.844

GnomAD3 exomes AF: 0.879 AC: 214784 AN: 244286 Hom.: 95042 AF XY: 0.880 AC XY: 117560 AN XY: 133598

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.900

Gnomad ASJ exome AF: 0.860

Gnomad EAS exome AF: 0.988

Gnomad SAS exome AF: 0.880

Gnomad FIN exome AF: 0.932

Gnomad NFE exome AF: 0.878

Gnomad OTH exome AF: 0.879

GnomAD4 exome AF: 0.875 AC: 1277376 AN: 1459618 Hom.: 560484 Cov.: 106 AF XY: 0.876 AC XY: 636062 AN XY: 726092

Gnomad4 AFR exome AF: 0.652

Gnomad4 AMR exome AF: 0.898

Gnomad4 ASJ exome AF: 0.856

Gnomad4 EAS exome AF: 0.992

Gnomad4 SAS exome AF: 0.877

Gnomad4 FIN exome AF: 0.936

Gnomad4 NFE exome AF: 0.875

Gnomad4 OTH exome AF: 0.868

GnomAD4 genome AF: 0.827 AC: 125752 AN: 152144 Hom.: 52802 Cov.: 36 AF XY: 0.832 AC XY: 61914 AN XY: 74380

Gnomad4 AFR AF: 0.666

Gnomad4 AMR AF: 0.876

Gnomad4 ASJ AF: 0.864

Gnomad4 EAS AF: 0.985

Gnomad4 SAS AF: 0.879

Gnomad4 FIN AF: 0.938

Gnomad4 NFE AF: 0.877

Gnomad4 OTH AF: 0.846

Alfa AF: 0.866 Hom.: 35325

Bravo AF: 0.815

Asia WGS AF: 0.928 AC: 3226 AN: 3478

EpiCase AF: 0.876

EpiControl AF: 0.869

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Distal arthrogryposis type 2B1 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1 Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	TNNI2 homepage - Leiden Muscular Dystrophy pages	-	- -

Arthrogryposis multiplex congenita Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.9
DANN	Benign	0.55

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

LitVar

Other links and lift over

dbSNP: rs907610; hg19: chr11-1861760; COSMIC: COSV53290568; COSMIC: COSV53290568;