1-201359173-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001276345.2(TNNT2):c.*37C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,598,354 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (12 hom.)
• Consequence: TNNT2 NM_001276345.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.565

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-201359173-G-A is Benign according to our data. Variant chr1-201359173-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 876211.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000519 (79/152308) while in subpopulation SAS AF= 0.00621 (30/4828). AF 95% confidence interval is 0.00447. There are 1 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.*37C>T		3_prime_UTR_variant	17/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.*37C>T		3_prime_UTR_variant	17/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00128 AC: 288 AN: 224264 Hom.: 7 AF XY: 0.00160 AC XY: 192 AN XY: 120374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000641

Gnomad ASJ exome AF: 0.00212

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00793

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000465

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.000787 AC: 1138 AN: 1446046 Hom.: 12 Cov.: 31 AF XY: 0.000973 AC XY: 698 AN XY: 717404

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000718

Gnomad4 ASJ exome AF: 0.00202

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.00723

Gnomad4 FIN exome AF: 0.0000762

Gnomad4 NFE exome AF: 0.000368

Gnomad4 OTH exome AF: 0.000935

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74484

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000812 Hom.: 0

Bravo AF: 0.000348

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TNNT2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Dilated cardiomyopathy 1D Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 12, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy, familial restrictive, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 12, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hypertrophic cardiomyopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 12, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.3
Dann	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs149240770; hg19: chr1-201328301; COSMIC: COSV99372500; COSMIC: COSV99372500;