11-1839995-C-A

Position:

• chr11-1839995-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003282.4(TNNI2):​c.15+140C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,304,916 control chromosomes in the GnomAD database, including 40,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3647 hom., cov: 32)
  • Exomes 𝑓: 0.25 (36554 hom.)
• Consequence: TNNI2 NM_003282.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.525

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-1839995-C-A is Benign according to our data. Variant chr11-1839995-C-A is described in ClinVar as [Benign]. Clinvar id is 140481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.15+140C>A		intron_variant		ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.15+140C>A		intron_variant			NP_001139301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.15+140C>A		intron_variant		2	NM_003282.4	ENSP00000371336.1
TNNI2	ENST00000252898.11	c.15+140C>A		intron_variant		3		ENSP00000252898.7
TNNI2	ENST00000381906.5	c.15+140C>A		intron_variant		3		ENSP00000371331.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31182 AN: 151964 Hom.: 3643 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.165

GnomAD4 exome AF: 0.246 AC: 283575 AN: 1152834 Hom.: 36554 AF XY: 0.247 AC XY: 140926 AN XY: 571256

Gnomad4 AFR exome AF: 0.0986

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.335

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.205 AC: 31193 AN: 152082 Hom.: 3647 Cov.: 32 AF XY: 0.211 AC XY: 15675 AN XY: 74330

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.167

Alfa AF: 0.231 Hom.: 2196

Bravo AF: 0.187

Asia WGS AF: 0.213 AC: 741 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
not provided, no classification provided	literature only	TNNI2 homepage - Leiden Muscular Dystrophy pages	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.1
DANN	Benign	0.87

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: rs1877444; hg19: chr11-1861225;