1-201368212-G-A

Variant names:

• chr1-201368212-G-A
• rs200754249
• NM_001276345.2:c.113C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001276345.2(TNNT2):​c.113C>T​(p.Ala38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,613,840 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 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. A38T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (2 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:14
• Conservation: PhyloP100: -0.0800
• Publications: 19 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0566774).
• BP6: Variant 1-201368212-G-A is Benign according to our data. Variant chr1-201368212-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43675.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000447 (68/152058) while in subpopulation AMR AF = 0.000983 (15/15266). AF 95% confidence interval is 0.000605. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.113C>T	p.Ala38Val	missense	Exon 6 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.113C>T	p.Ala38Val	missense	Exon 6 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.113C>T	p.Ala38Val	missense	Exon 6 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.113C>T	p.Ala38Val	missense	Exon 6 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.83C>T	p.Ala28Val	missense	Exon 5 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.113C>T	p.Ala38Val	missense	Exon 6 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000453 AC: 114 AN: 251402 AF XY: 0.000456

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000583 AC: 852 AN: 1461782 Hom.: 2 Cov.: 32 AF XY: 0.000575 AC XY: 418 AN XY: 727196

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.000514 AC: 23 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86256

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53374

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.000687 AC: 764 AN: 1111972

Other (OTH) AF: 0.000563 AC: 34 AN: 60390

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74268

African (AFR) AF: 0.0000725 AC: 3 AN: 41392

American (AMR) AF: 0.000983 AC: 15 AN: 15266

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

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

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

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

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68020

Other (OTH) AF: 0.00192 AC: 4 AN: 2082

Alfa AF: 0.000667 Hom.: 0

Bravo AF: 0.000631

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.00109

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Cardiomyopathy (2)
-	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	-	Hypertrophic cardiomyopathy 2 (1)
-	1	-	Increased left ventricular wall thickness (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)
-	-	1	Supraventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
CardioboostCm	Benign	0.0054
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	9.8
DANN	Benign	0.82
DEOGEN2	Benign	0.40	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.057	T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	-0.070	N
PhyloP100		-0.080
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.23	N
REVEL	Uncertain	0.61
Sift	Benign	0.10	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.61
MPC		0.51
ClinPred		0.0010	T
GERP RS		-1.3
Varity_R		0.023
gMVP		0.41
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs200754249; hg19: chr1-201337340;