rs540630390

chr1-201369850-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001276345.2(TNNT2):c.68-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,188 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (45 hom.)
• Consequence: TNNT2 NM_001276345.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0008642
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.884

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-201369850-G-A is Benign according to our data. Variant chr1-201369850-G-A is described in ClinVar as [Benign]. Clinvar id is 810755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201369850-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00186 (284/152330) while in subpopulation EAS AF= 0.0441 (229/5190). AF 95% confidence interval is 0.0394. There are 7 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 285 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.68-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.68-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001276345.2	A2

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152212 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0440

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00387 AC: 972 AN: 251422 Hom.: 21 AF XY: 0.00386 AC XY: 525 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0450

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00177 AC: 2592 AN: 1461858 Hom.: 45 Cov.: 35 AF XY: 0.00178 AC XY: 1295 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0509

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.00148

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00186 AC: 284 AN: 152330 Hom.: 7 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74496

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0441

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000642 Hom.: 0

Bravo AF: 0.00197

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Dilated cardiomyopathy 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy;C0520806:Sudden unexplained death Benign:1

Benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Oct 12, 2018

TNNT2 c.68-5C>T was identified in a HCM, DCM and sudden unexplained death proband, however it is very common in population databases such as the Genome Aggregation Database (AF=0.0036; http://gnomad.broadinstitute.org/), therefore we classify this variant as 'benign'. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 23, 2023

- -

Cardiomyopathy, familial restrictive, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Hypertrophic cardiomyopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	11
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00086
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs540630390; hg19: chr1-201338978;