rs35559054

Variant names:

• chr1-201364468-TG-T
• rs35559054
• NM_001276345.2:c.412-94delC

Your query was ambiguous. Multiple possible variants found:

• chr1-201364468-TG-T
• chr1-201364468-TG-TGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001276345.2(TNNT2):​c.412-94delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,303,710 control chromosomes in the GnomAD database, including 95 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (86 hom.)
• Consequence: TNNT2 NM_001276345.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.134
• Publications: 0 publications found

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

TNNT2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000286600 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-201364468-TG-T is Benign according to our data. Variant chr1-201364468-TG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 496075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00827 (1260/152336) while in subpopulation NFE AF = 0.012 (818/68024). AF 95% confidence interval is 0.0113. There are 9 homozygotes in GnomAd4. There are 636 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276345.2. 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
	TNNT2	NM_001276345.2	MANE Select	c.412-94delC		intron	N/A	NP_001263274.1
	TNNT2	NM_000364.4		c.412-94delC		intron	N/A	NP_000355.2
	TNNT2	NM_001406723.1		c.412-94delC		intron	N/A	NP_001393652.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.412-94delC		intron	N/A	ENSP00000499593.1
	TNNT2	ENST00000367322.6	TSL:1	c.379-94delC		intron	N/A	ENSP00000356291.2
	TNNT2	ENST00000367320.6	TSL:1	c.292-94delC		intron	N/A	ENSP00000356289.2

Frequencies

GnomAD3 genomes AF: 0.00828 AC: 1260 AN: 152218 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00962 AC: 11079 AN: 1151374 Hom.: 86 AF XY: 0.00925 AC XY: 5374 AN XY: 581196

African (AFR) AF: 0.00139 AC: 38 AN: 27242

American (AMR) AF: 0.00199 AC: 74 AN: 37254

Ashkenazi Jewish (ASJ) AF: 0.00401 AC: 95 AN: 23714

East Asian (EAS) AF: 0.00 AC: 0 AN: 35660

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75650

European-Finnish (FIN) AF: 0.0255 AC: 931 AN: 36452

Middle Eastern (MID) AF: 0.00305 AC: 16 AN: 5244

European-Non Finnish (NFE) AF: 0.0112 AC: 9592 AN: 860082

Other (OTH) AF: 0.00663 AC: 332 AN: 50076

GnomAD4 genome AF: 0.00827 AC: 1260 AN: 152336 Hom.: 9 Cov.: 33 AF XY: 0.00854 AC XY: 636 AN XY: 74496

African (AFR) AF: 0.00214 AC: 89 AN: 41592

American (AMR) AF: 0.00274 AC: 42 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0276 AC: 293 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 818 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.0114 Hom.: 0

Bravo AF: 0.00661

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiomyopathy, familial restrictive, 3 (1)
-	-	1	Dilated cardiomyopathy 1D (1)
-	-	1	Hypertrophic cardiomyopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs35559054; hg19: chr1-201333596;