chr1-201359221-G-A

Variant names:

• chr1-201359221-G-A
• rs367785431
• NM_001276345.2:c.886C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP3 PP5

The NM_001276345.2(TNNT2):​c.886C>T​(p.Arg296Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,610,372 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R296S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:6
• Conservation: PhyloP100: 3.54
• Publications: 20 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 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201359221-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 577168.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786
• PP5: Variant 1-201359221-G-A is Pathogenic according to our data. Variant chr1-201359221-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43676.

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.886C>T	p.Arg296Cys	missense	Exon 17 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.877C>T	p.Arg293Cys	missense	Exon 16 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.877C>T	p.Arg293Cys	missense	Exon 16 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.886C>T	p.Arg296Cys	missense	Exon 17 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.844C>T	p.Arg282Cys	missense	Exon 15 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.757C>T	p.Arg253Cys	missense	Exon 15 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000247 AC: 6 AN: 242990 AF XY: 0.0000305

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1458206 Hom.: 1 Cov.: 31 AF XY: 0.0000166 AC XY: 12 AN XY: 724788

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39624

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53206

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5664

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1110956

Other (OTH) AF: 0.0000332 AC: 2 AN: 60280

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000198 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostCm	Uncertain	0.57
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.77		Gain of catalytic residue at W297 (P = 5e-04)
MVP		0.97
MPC		1.7
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.11
gMVP		0.50
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367785431; hg19: chr1-201328349; COSMIC: COSV52664595; COSMIC: COSV52664595;