rs537595753

Positions:

chr17-39665391-CGGA-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS1

The NM_003673.4(TCAP):c.37_39delGAG(p.Glu13del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00119 in 1,613,638 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E13E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

TCAP
NM_003673.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: 5.92

Variant links:

Genes affected

TCAP (HGNC:11610): (titin-cap) Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]

TCAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_003673.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 17-39665391-CGGA-C is Benign according to our data. Variant chr17-39665391-CGGA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44707.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=1, Benign=5}. Variant chr17-39665391-CGGA-C is described in Lovd as [Likely_benign]. Variant chr17-39665391-CGGA-C is described in Lovd as [Benign]. Variant chr17-39665391-CGGA-C is described in Lovd as [Pathogenic]. Variant chr17-39665391-CGGA-C is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000947 (144/152134) while in subpopulation NFE AF= 0.00153 (104/67986). AF 95% confidence interval is 0.00129. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4 linkuse as main transcript	c.37_39delGAG	p.Glu13del	conservative_inframe_deletion	1/2	ENST00000309889.3	NP_003664.1	O15273A2TDC0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3 linkuse as main transcript	c.37_39delGAG	p.Glu13del	conservative_inframe_deletion	1/2	1	NM_003673.4	ENSP00000312624.2		O15273
TCAP	ENST00000578283.1 linkuse as main transcript	c.37_39delGAG	p.Glu13del	conservative_inframe_deletion	1/3	5		ENSP00000462787.1		J3KT40

Frequencies

GnomAD3 genomes

AF:

0.000947

AC:

144

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00153

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00100

AC:

251

AN:

251088

Hom.:

AF XY:

0.00101

AC XY:

137

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00428

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00122

AC:

1776

AN:

1461504

Hom.:

AF XY:

0.00123

AC XY:

891

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00371

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.000960

Gnomad4 NFE exome

AF:

0.00134

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.000947

AC:

144

AN:

152134

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00153

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.000990

EpiCase

AF:

0.00153

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 10, 2019	The p.Glu13del variant in TCAP is classified as benign because it has been identified in 0.4% (43/10340) of Ashkenazi Jewish chromosomes (including one homozygote) and in 0.1% (182/128862) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2018	Variant summary: TCAP c.37_39delGAG (p.Glu13del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.001 in 276952 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 40-fold of the estimated maximal expected allele frequency for a pathogenic variant in TCAP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.37_39delGAG, has been reported in the literature in individuals affected with Cardiomyopathy as well as in controls (Marziliano_2006, Perrot_2006). In vitro studies have shown the variant to result in the inability to bind the titin N-terminus due to the loss of proper formation of the telethonin B-hairpin structure, which the authors state may in fact be harmless (Knoll_2011). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. One cardiology center (via ClinVar), reports the variant in HCM family members who also carried a pathogenic MYBPC3 variant, and in another family, the variant did not segregate with disease in all affected family members. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 02, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 20, 2017	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TCAP: PM4:Supporting, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2014	The variant is found in DCM,CARDIOMYOPATHY panel(s). -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 08, 2018

- -

Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BS1, BS2, PM4 -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypertrophic cardiomyopathy 25

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hypertrophic cardiomyopathy 1

Benign:1

Benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 16, 2017

The TCAP Glu13del variant has been previously identified in multiple HCM and DCM patients (Bos JM, et al., 2006; Perrot A, et al., 2006; Marziliano N, et al., 2006; Anderson PS, et al., 2009; Hirtle-Lewis M, et al., 2013; Pugh TJ, et al., 2014), however it has also been identified control cohorts at an allele frequency of up to 0.5% (Perrot A, et al., 2006; Marziliano N, et al., 2006; Anderson PS, et al., 2009). In vitro functional evaluations have shown that the TCAP Glu13del variant causes improper formation of telethonin Î²-hairpin structure necessary for titin binding, that may in fact be harmless (Knoll R, et al., 2011). The variant is present in the Exome Aggregation Consortium dataset (MAF= 0.00095; http://exac.broadinstitute.org/). We identified this variant in 3 HCM probands. In one of these families both the proband and an affected family member also carried a second pathogenic variant (MYBPC3 p.Pro955Argfs*95). In another family it was found to cosegregate in two affected family members, but did not segregate to a third affected family member. In summary, based on identification of the variant in controls, high allele frequency, as well as the lack of segregation in our family, we classify TCAP Glu13del as a "benign" variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over