rs397516454

chr1-201365610-A-Cchr1-201365610-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001276345.2(TNNT2):c.294T>G(p.Asp98Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense, splice_region
• Scores: Splicing: ADA: 0.00004981
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.573

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-201365610-A-C is Pathogenic according to our data. Variant chr1-201365610-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43625.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.294T>G	p.Asp98Glu	missense_variant, splice_region_variant	9/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.294T>G	p.Asp98Glu	missense_variant, splice_region_variant	9/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 04, 2015

The p.Asp88Glu variant in TNTT2 has been identified by our laboratory in 1 Cauca sian infant with DCM but not in large population studies. This variant is locate d in the last base of the exon, which is part of the 5' splice region. Computati onal tools do not suggest an impact to splicing. However, this information is no t predictive enough to rule out pathogenicity. Aspartic acid (Asp) at position 8 8 is highly conserved in mammals and across evolutionarily distant species and t he change to glutamic acid (Glu) was predicted to be pathogenic using a computat ional tool clinically validated by our laboratory. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). In summary, altho ugh additional studies are required to fully establish its clinical significance , the p.Asp88Glu variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Uncertain	0.82
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.2	D;D;.;.;.;.;.;.;D;D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.060	T;T;.;.;.;.;.;.;T;T;T;D;D;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T;.;T;T;.
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;D;.;.;.
Vest4		0.59
MutPred		0.30		.;.;.;.;Loss of stability (P = 0.1561);.;.;.;.;.;.;Loss of stability (P = 0.1561);.;.;
MVP		0.93
MPC		1.4
ClinPred		0.99	D
GERP RS		-3.6
Varity_R		0.38
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.32
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

Publications

LitVar

Other links and lift over

dbSNP: rs397516454; hg19: chr1-201334738;