1-201368042-A-T

Variant names:

• chr1-201368042-A-T
• rs3729842
• NM_001276345.2:c.163+120T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001276345.2(TNNT2):​c.163+120T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNNT2 NM_001276345.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.157
• Publications: 14 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.163+120T>A		intron	N/A	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.163+120T>A		intron	N/A	NP_000355.2
	TNNT2	NM_001406723.1		c.163+120T>A		intron	N/A	NP_001393652.1	P45379-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.163+120T>A		intron	N/A	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.133+120T>A		intron	N/A	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.163+120T>A		intron	N/A	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000105 AC: 1 AN: 949684 Hom.: 0 AF XY: 0.00000202 AC XY: 1 AN XY: 494274

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23386

American (AMR) AF: 0.00 AC: 0 AN: 43394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22850

East Asian (EAS) AF: 0.00 AC: 0 AN: 37386

South Asian (SAS) AF: 0.00 AC: 0 AN: 75430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4220

European-Non Finnish (NFE) AF: 0.00000154 AC: 1 AN: 647774

Other (OTH) AF: 0.00 AC: 0 AN: 43552

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.4
DANN	Benign	0.59
PhyloP100		-0.16

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: rs3729842; hg19: chr1-201337170;