rs185908824

Variant names:

• chr11-1840957-C-T
• rs185908824
• NM_003282.4:c.276+49C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-1840957-C-T
• chr11-1840957-C-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003282.4(TNNI2):​c.276+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,594,542 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: TNNI2 NM_003282.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45
• Publications: 0 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-1840957-C-T is Benign according to our data. Variant chr11-1840957-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 259024.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI2	NM_003282.4	MANE Select	c.276+49C>T		intron	N/A	NP_003273.1	P48788-1
	TNNI2	NM_001145829.2		c.276+49C>T		intron	N/A	NP_001139301.1	P48788-1
	TNNI2	NM_001145841.2		c.276+49C>T		intron	N/A	NP_001139313.1	P48788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI2	ENST00000381911.6	TSL:2 MANE Select	c.276+49C>T		intron	N/A	ENSP00000371336.1	P48788-1
	TNNI2	ENST00000252898.11	TSL:3	c.276+49C>T		intron	N/A	ENSP00000252898.7	P48788-1
	TNNI2	ENST00000381905.3	TSL:3	c.276+49C>T		intron	N/A	ENSP00000371330.3	P48788-2

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152062 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00138 AC: 296 AN: 214188 AF XY: 0.00133

Gnomad AFR exome AF: 0.000333

Gnomad AMR exome AF: 0.000288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000522

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00259 AC: 3734 AN: 1442366 Hom.: 11 Cov.: 34 AF XY: 0.00244 AC XY: 1750 AN XY: 716030

African (AFR) AF: 0.000546 AC: 18 AN: 32996

American (AMR) AF: 0.000262 AC: 11 AN: 42028

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 38640

South Asian (SAS) AF: 0.000165 AC: 14 AN: 84704

European-Finnish (FIN) AF: 0.000533 AC: 27 AN: 50630

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5692

European-Non Finnish (NFE) AF: 0.00322 AC: 3546 AN: 1102558

Other (OTH) AF: 0.00195 AC: 116 AN: 59500

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74386

African (AFR) AF: 0.000674 AC: 28 AN: 41522

American (AMR) AF: 0.000392 AC: 6 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000505 Hom.: 0

Bravo AF: 0.00153

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.3
DANN	Benign	0.87
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs185908824; hg19: chr11-1862187;