rs1877444

Variant names:

• chr11-1839995-C-A
• rs1877444
• NM_003282.4:c.15+140C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• distal arthrogryposis type 2B1

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.15+140C>A		intron_variant	Intron 3 of 7	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.15+140C>A		intron_variant	Intron 3 of 7		NP_001139301.1
TNNI2	NM_001145841.2	c.-229C>A		upstream_gene_variant			NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.15+140C>A		intron_variant	Intron 3 of 7	2	NM_003282.4	ENSP00000371336.1

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

African (AFR) AF: 0.0986 AC: 2616 AN: 26538

American (AMR) AF: 0.182 AC: 5430 AN: 29800

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 2970 AN: 19806

East Asian (EAS) AF: 0.240 AC: 8440 AN: 35216

South Asian (SAS) AF: 0.251 AC: 17101 AN: 68248

European-Finnish (FIN) AF: 0.335 AC: 12180 AN: 36404

Middle Eastern (MID) AF: 0.147 AC: 701 AN: 4756

European-Non Finnish (NFE) AF: 0.253 AC: 223061 AN: 882638

Other (OTH) AF: 0.224 AC: 11076 AN: 49428

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

African (AFR) AF: 0.104 AC: 4318 AN: 41506

American (AMR) AF: 0.176 AC: 2688 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 520 AN: 3468

East Asian (EAS) AF: 0.236 AC: 1218 AN: 5154

South Asian (SAS) AF: 0.244 AC: 1176 AN: 4824

European-Finnish (FIN) AF: 0.364 AC: 3844 AN: 10566

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16891 AN: 67948

Other (OTH) AF: 0.167 AC: 353 AN: 2114

Alfa AF: 0.225 Hom.: 3178

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

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

TNNI2 homepage - Leiden Muscular Dystrophy pages

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.1
DANN	Benign	0.87
PhyloP100		-0.53
PromoterAI		0.084	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1877444; hg19: chr11-1861225;