rs397516862

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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).

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

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 25
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
autosomal recessive limb-girdle muscular dystrophy type 2G
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TCAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 VariationId is 44707.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCAP	NM_003673.4 link	c.37_39delGAG	p.Glu13del	conservative_inframe_deletion	Exon 1 of 2	ENST00000309889.3	NP_003664.1	O15273A2TDC0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3 link	c.37_39delGAG	p.Glu13del	conservative_inframe_deletion	Exon 1 of 2	1	NM_003673.4	ENSP00000312624.2		O15273
TCAP	ENST00000578283.1 link	c.37_39delGAG	p.Glu13del	conservative_inframe_deletion	Exon 1 of 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

GnomAD2 exomes

AF:

0.00100

AC:

251

AN:

251088

AF XY:

0.00101

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 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

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000581

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00371

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000960

AC:

AN:

53124

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00134

AC:

1486

AN:

1111962

Other (OTH)

AF:

0.00136

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

192

289

385

481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000947

AC:

144

AN:

152134

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000386

AC:

AN:

41488

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00153

AC:

104

AN:

67986

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Sep 03, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 10, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 02, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 28, 2014

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is found in DCM,CARDIOMYOPATHY panel(s). -

Feb 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TCAP: PM4:Supporting, BS2 -

Cardiomyopathy

Benign:1

Mar 08, 2018

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Criteria: BS1, BS2, PM4 -

Hypertrophic cardiomyopathy 25

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 06, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 1

Benign:1

Mar 16, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

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

PhyloP100

5.9

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over