chr1-201365603-C-T

Variant names:

• chr1-201365603-C-T
• rs45490292
• NM_001276345.2:c.294+7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001276345.2(TNNT2):​c.294+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,882 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (15 hom.)
• Consequence: TNNT2 NM_001276345.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003630
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.0460
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-201365603-C-T is Benign according to our data. Variant chr1-201365603-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00976 (1487/152296) while in subpopulation AFR AF = 0.033 (1370/41570). AF 95% confidence interval is 0.0315. There are 24 homozygotes in GnomAd4. There are 698 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.294+7G>A		splice_region intron	N/A	NP_001263274.1
	TNNT2	NM_000364.4		c.294+7G>A		splice_region intron	N/A	NP_000355.2
	TNNT2	NM_001406723.1		c.294+7G>A		splice_region intron	N/A	NP_001393652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.294+7G>A		splice_region intron	N/A	ENSP00000499593.1
	TNNT2	ENST00000367322.6	TSL:1	c.261+7G>A		splice_region intron	N/A	ENSP00000356291.2
	TNNT2	ENST00000367320.6	TSL:1	c.291+7G>A		splice_region intron	N/A	ENSP00000356289.2

Frequencies

GnomAD3 genomes AF: 0.00975 AC: 1483 AN: 152178 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00242 AC: 608 AN: 250820 AF XY: 0.00184

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00103 AC: 1499 AN: 1461586 Hom.: 15 Cov.: 31 AF XY: 0.000854 AC XY: 621 AN XY: 727064

African (AFR) AF: 0.0327 AC: 1095 AN: 33472

American (AMR) AF: 0.00197 AC: 88 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26128

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

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000119 AC: 132 AN: 1111850

Other (OTH) AF: 0.00260 AC: 157 AN: 60390

GnomAD4 genome AF: 0.00976 AC: 1487 AN: 152296 Hom.: 24 Cov.: 32 AF XY: 0.00937 AC XY: 698 AN XY: 74458

African (AFR) AF: 0.0330 AC: 1370 AN: 41570

American (AMR) AF: 0.00536 AC: 82 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

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: 0.000220 AC: 15 AN: 68030

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00824 Hom.: 17

Bravo AF: 0.0113

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Hypertrophic 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	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Familial restrictive 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
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.1
DANN	Benign	0.68
PhyloP100		-0.046
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.024
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: rs45490292; hg19: chr1-201334731;