chr1-201361301-T-C

Variant names:

• chr1-201361301-T-C
• rs3730238
• NM_001276345.2:c.788A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001276345.2(TNNT2):​c.788A>G​(p.Lys263Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0322 in 1,614,024 control chromosomes in the GnomAD database, including 2,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.061 (558 hom., cov: 32)
  • Exomes 𝑓: 0.029 (1812 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 4.04
• Publications: 33 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: Benign. The variant received -18 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, 24 uncertain in NM_001276345.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016825795).
• BP6: Variant 1-201361301-T-C is Benign according to our data. Variant chr1-201361301-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

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.788A>G	p.Lys263Arg	missense	Exon 15 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.779A>G	p.Lys260Arg	missense	Exon 14 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.779A>G	p.Lys260Arg	missense	Exon 14 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.788A>G	p.Lys263Arg	missense	Exon 15 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.746A>G	p.Lys249Arg	missense	Exon 13 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.659A>G	p.Lys220Arg	missense	Exon 13 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes AF: 0.0613 AC: 9318 AN: 152076 Hom.: 557 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0455

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0520

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0393

GnomAD2 exomes AF: 0.0470 AC: 11810 AN: 251476 AF XY: 0.0495

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.0449

Gnomad FIN exome AF: 0.0523

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0428

GnomAD4 exome AF: 0.0292 AC: 42719 AN: 1461830 Hom.: 1812 Cov.: 31 AF XY: 0.0322 AC XY: 23447 AN XY: 727222

African (AFR) AF: 0.160 AC: 5345 AN: 33474

American (AMR) AF: 0.0217 AC: 970 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 511 AN: 26134

East Asian (EAS) AF: 0.0482 AC: 1914 AN: 39700

South Asian (SAS) AF: 0.141 AC: 12183 AN: 86258

European-Finnish (FIN) AF: 0.0559 AC: 2988 AN: 53410

Middle Eastern (MID) AF: 0.0374 AC: 216 AN: 5768

European-Non Finnish (NFE) AF: 0.0147 AC: 16363 AN: 1111972

Other (OTH) AF: 0.0369 AC: 2229 AN: 60392

GnomAD4 genome AF: 0.0613 AC: 9326 AN: 152194 Hom.: 558 Cov.: 32 AF XY: 0.0641 AC XY: 4774 AN XY: 74420

African (AFR) AF: 0.149 AC: 6178 AN: 41504

American (AMR) AF: 0.0257 AC: 393 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

East Asian (EAS) AF: 0.0456 AC: 236 AN: 5172

South Asian (SAS) AF: 0.154 AC: 741 AN: 4820

European-Finnish (FIN) AF: 0.0520 AC: 552 AN: 10616

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1054 AN: 67998

Other (OTH) AF: 0.0398 AC: 84 AN: 2110

Alfa AF: 0.0291 Hom.: 714

Bravo AF: 0.0607

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.149 AC: 656

ESP6500EA AF: 0.0148 AC: 127

ExAC AF: 0.0507 AC: 6159

Asia WGS AF: 0.0920 AC: 318 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0145

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Cardiomyopathy (3)
-	-	3	not provided (3)
-	-	1	Cardiomyopathy, familial restrictive, 3 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1D (1)
-	-	1	Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Familial restrictive cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 2 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Benign	0.86	T
Polyphen		0.0050	B
Vest4		0.14
MPC		0.42
ClinPred		0.021	T
GERP RS		2.6
Varity_R		0.25
gMVP		0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs3730238; hg19: chr1-201330429; COSMIC: COSV52663248; COSMIC: COSV52663248;