rs45576635

Variant names:

• chr1-201359577-G-A
• rs45576635
• NM_001276345.2:c.851+46C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001276345.2(TNNT2):​c.851+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,562,712 control chromosomes in the GnomAD database, including 708 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.020 (46 hom., cov: 32)
  • Exomes 𝑓: 0.028 (662 hom.)
• Consequence: TNNT2 NM_001276345.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00800
• Publications: 8 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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 2

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

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0198 (3022/152306) while in subpopulation NFE AF = 0.0298 (2030/68020). AF 95% confidence interval is 0.0288. There are 46 homozygotes in GnomAd4. There are 1334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.851+46C>T		intron_variant	Intron 16 of 16	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.851+46C>T		intron_variant	Intron 16 of 16		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3023 AN: 152188 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00553

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0248

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0216 AC: 4550 AN: 211120 AF XY: 0.0224

Gnomad AFR exome AF: 0.00421

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0340

Gnomad EAS exome AF: 0.0000623

Gnomad FIN exome AF: 0.00965

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0265

GnomAD4 exome AF: 0.0280 AC: 39544 AN: 1410406 Hom.: 662 Cov.: 28 AF XY: 0.0280 AC XY: 19617 AN XY: 700346

African (AFR) AF: 0.00448 AC: 144 AN: 32130

American (AMR) AF: 0.0187 AC: 776 AN: 41598

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 876 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 38426

South Asian (SAS) AF: 0.0208 AC: 1702 AN: 81916

European-Finnish (FIN) AF: 0.0110 AC: 566 AN: 51554

Middle Eastern (MID) AF: 0.0363 AC: 207 AN: 5706

European-Non Finnish (NFE) AF: 0.0314 AC: 33738 AN: 1074934

Other (OTH) AF: 0.0262 AC: 1535 AN: 58584

GnomAD4 genome AF: 0.0198 AC: 3022 AN: 152306 Hom.: 46 Cov.: 32 AF XY: 0.0179 AC XY: 1334 AN XY: 74478

African (AFR) AF: 0.00551 AC: 229 AN: 41548

American (AMR) AF: 0.0247 AC: 378 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4832

European-Finnish (FIN) AF: 0.00894 AC: 95 AN: 10624

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2030 AN: 68020

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0270 Hom.: 23

Bravo AF: 0.0210

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.73
PhyloP100		-0.0080
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: rs45576635; hg19: chr1-201328705;