rs112517111

Positions:

• chr11-1841014-G-A
• chr11-1841014-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_003282.4(TNNI2):​c.277-17G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,610,828 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (50 hom.)
• Consequence: TNNI2 NM_003282.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.716

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 11-1841014-G-A is Benign according to our data. Variant chr11-1841014-G-A is described in ClinVar as [Benign]. Clinvar id is 259025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1841014-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2182/152238) while in subpopulation AFR AF= 0.0498 (2069/41542). AF 95% confidence interval is 0.048. There are 72 homozygotes in gnomad4. There are 1015 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI2	NM_003282.4	c.277-17G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000381911.6
TNNI2	NM_001145829.2	c.277-17G>A		splice_polypyrimidine_tract_variant, intron_variant
TNNI2	NM_001145841.2	c.277-17G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI2	ENST00000381911.6	c.277-17G>A		splice_polypyrimidine_tract_variant, intron_variant		2	NM_003282.4	A1
TNNI2	ENST00000252898.11	c.277-17G>A		splice_polypyrimidine_tract_variant, intron_variant		3		A1
TNNI2	ENST00000381905.3	c.277-17G>A		splice_polypyrimidine_tract_variant, intron_variant		3		P4
TNNI2	ENST00000381906.5	c.277-17G>A		splice_polypyrimidine_tract_variant, intron_variant		3		A1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2175 AN: 152120 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00344 AC: 827 AN: 240304 Hom.: 26 AF XY: 0.00252 AC XY: 332 AN XY: 131982

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000409

Gnomad EAS exome AF: 0.0000564

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000139

Gnomad OTH exome AF: 0.00240

GnomAD4 exome AF: 0.00149 AC: 2168 AN: 1458590 Hom.: 50 Cov.: 34 AF XY: 0.00127 AC XY: 919 AN XY: 725470

Gnomad4 AFR exome AF: 0.0511

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000720

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.0143 AC: 2182 AN: 152238 Hom.: 72 Cov.: 33 AF XY: 0.0136 AC XY: 1015 AN XY: 74428

Gnomad4 AFR AF: 0.0498

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00779 Hom.: 6

Bravo AF: 0.0165

Asia WGS AF: 0.00549 AC: 19 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Distal arthrogryposis type 2B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.6
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.73		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs112517111; hg19: chr11-1862244;