1-201365211-C-T

Variant names:

• chr1-201365211-C-T
• rs537067344
• NM_001276345.2:c.391G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_001276345.2(TNNT2):​c.391G>A​(p.Val131Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V131L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0570
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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 -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_001276345.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.023067683).
• BP6: Variant 1-201365211-C-T is Benign according to our data. Variant chr1-201365211-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 571790.

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.391G>A	p.Val131Ile	missense	Exon 10 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.391G>A	p.Val131Ile	missense	Exon 10 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.391G>A	p.Val131Ile	missense	Exon 10 of 16	NP_001393652.1	P45379-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.391G>A	p.Val131Ile	missense	Exon 10 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.358G>A	p.Val120Ile	missense	Exon 9 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.291+399G>A		intron	N/A	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000915 AC: 23 AN: 251496 AF XY: 0.0000809

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461750 Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 34 AN XY: 727198

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111884

Other (OTH) AF: 0.000132 AC: 8 AN: 60392

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74472

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000355 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
CardioboostCm	Benign	0.043
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.47
DANN	Benign	0.58
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-0.057
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.14
MutPred		0.27		Gain of methylation at K134 (P = 0.0897)
MVP		0.55
MPC		0.41
ClinPred		0.018	T
GERP RS		-10
Varity_R		0.057
gMVP		0.43
Mutation Taster		=98/2	polymorphism

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: rs537067344; hg19: chr1-201334339; COSMIC: COSV52661947; COSMIC: COSV52661947;