chr1-201367856-C-T

Variant names:

• chr1-201367856-C-T
• rs3729843
• NM_001276345.2:c.164-50G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001276345.2(TNNT2):​c.164-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,606,412 control chromosomes in the GnomAD database, including 151,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11003 hom., cov: 32)
  • Exomes 𝑓: 0.43 (140411 hom.)
• Consequence: TNNT2 NM_001276345.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.359
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-201367856-C-T is Benign according to our data. Variant chr1-201367856-C-T is described in ClinVar as Benign. ClinVar VariationId is 256843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.164-50G>A		intron	N/A	NP_001263274.1
	TNNT2	NM_000364.4		c.164-50G>A		intron	N/A	NP_000355.2
	TNNT2	NM_001406723.1		c.164-50G>A		intron	N/A	NP_001393652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.164-50G>A		intron	N/A	ENSP00000499593.1
	TNNT2	ENST00000367322.6	TSL:1	c.134-53G>A		intron	N/A	ENSP00000356291.2
	TNNT2	ENST00000367320.6	TSL:1	c.164-53G>A		intron	N/A	ENSP00000356289.2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51760 AN: 151840 Hom.: 10991 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.342

GnomAD2 exomes AF: 0.418 AC: 105001 AN: 251296 AF XY: 0.425

Gnomad AFR exome AF: 0.0714

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.438

GnomAD4 exome AF: 0.433 AC: 629887 AN: 1454454 Hom.: 140411 Cov.: 29 AF XY: 0.435 AC XY: 314744 AN XY: 724020

African (AFR) AF: 0.0657 AC: 2184 AN: 33254

American (AMR) AF: 0.512 AC: 22881 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 10771 AN: 26104

East Asian (EAS) AF: 0.204 AC: 8101 AN: 39642

South Asian (SAS) AF: 0.434 AC: 37355 AN: 86116

European-Finnish (FIN) AF: 0.479 AC: 25488 AN: 53256

Middle Eastern (MID) AF: 0.380 AC: 2184 AN: 5746

European-Non Finnish (NFE) AF: 0.449 AC: 496199 AN: 1105480

Other (OTH) AF: 0.411 AC: 24724 AN: 60136

GnomAD4 genome AF: 0.341 AC: 51782 AN: 151958 Hom.: 11003 Cov.: 32 AF XY: 0.345 AC XY: 25612 AN XY: 74254

African (AFR) AF: 0.0814 AC: 3379 AN: 41496

American (AMR) AF: 0.454 AC: 6919 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1395 AN: 3466

East Asian (EAS) AF: 0.202 AC: 1041 AN: 5160

South Asian (SAS) AF: 0.421 AC: 2023 AN: 4804

European-Finnish (FIN) AF: 0.490 AC: 5174 AN: 10552

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30754 AN: 67904

Other (OTH) AF: 0.342 AC: 723 AN: 2114

Alfa AF: 0.383 Hom.: 21760

Bravo AF: 0.327

Asia WGS AF: 0.325 AC: 1131 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1D Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy, familial restrictive, 3 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy 2 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.84
PhyloP100		0.36
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: rs3729843; hg19: chr1-201336984; COSMIC: COSV52662970; COSMIC: COSV52662970;