1-201361940-A-G

Variant names:

• chr1-201361940-A-G
• rs45520032
• NM_001276345.2:c.692T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_Moderate BP6

The NM_001276345.2(TNNT2):​c.692T>C​(p.Ile231Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I231V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:4
• Conservation: PhyloP100: 7.39
• Publications: 8 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• BP6: Variant 1-201361940-A-G is Benign according to our data. Variant chr1-201361940-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181604.

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.692T>C	p.Ile231Thr	missense	Exon 14 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.683T>C	p.Ile228Thr	missense	Exon 13 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.683T>C	p.Ile228Thr	missense	Exon 13 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.692T>C	p.Ile231Thr	missense	Exon 14 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.650T>C	p.Ile217Thr	missense	Exon 12 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.563T>C	p.Ile188Thr	missense	Exon 12 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000143 AC: 36 AN: 251490 AF XY: 0.000125

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000155 AC: 227 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.000143 AC XY: 104 AN XY: 727246

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1111998

Other (OTH) AF: 0.000215 AC: 13 AN: 60396

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74462

African (AFR) AF: 0.0000722 AC: 3 AN: 41560

American (AMR) AF: 0.000392 AC: 6 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000202 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
CardioboostCm	Benign	0.054
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.035	D
Polyphen		0.98	D
Vest4		0.69
MVP		0.94
MPC		1.1
ClinPred		0.86	D
GERP RS		4.4
Varity_R		0.72
gMVP		0.79
Mutation Taster		=0/100	disease causing

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: rs45520032; hg19: chr1-201331068;