chr17-39665921-C-T

Position:

chr17-39665921-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000309889.3(TCAP):c.316C>T(p.Arg106Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00847 in 1,612,818 control chromosomes in the GnomAD database, including 622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0081 ( 38 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 584 hom. )

Consequence

TCAP
ENST00000309889.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: 1.29

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031297505).

BP6

Variant 17-39665921-C-T is Benign according to our data. Variant chr17-39665921-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-39665921-C-T is described in Lovd as [Benign]. Variant chr17-39665921-C-T is described in Lovd as [Likely_benign]. Variant chr17-39665921-C-T is described in Lovd as [Likely_pathogenic].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4 linkuse as main transcript	c.316C>T	p.Arg106Cys	missense_variant	2/2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3 linkuse as main transcript	c.316C>T	p.Arg106Cys	missense_variant	2/2	1	NM_003673.4	ENSP00000312624	P1
TCAP	ENST00000578283.1 linkuse as main transcript	c.244C>T	p.Arg82Cys	missense_variant	3/3	5		ENSP00000462787

Frequencies

GnomAD3 genomes

AF:

0.00805

AC:

1225

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0500

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00487

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.0239

AC:

5952

AN:

248892

Hom.:

514

AF XY:

0.0186

AC XY:

2509

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.00200

Gnomad AMR exome

AF:

0.152

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.000328

Gnomad NFE exome

AF:

0.00427

Gnomad OTH exome

AF:

0.0189

GnomAD4 exome

AF:

0.00851

AC:

12435

AN:

1460484

Hom.:

584

Cov.:

AF XY:

0.00767

AC XY:

5574

AN XY:

726590

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.137

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00183

Gnomad4 FIN exome

AF:

0.000402

Gnomad4 NFE exome

AF:

0.00508

Gnomad4 OTH exome

AF:

0.00624

GnomAD4 genome

AF:

0.00808

AC:

1231

AN:

152334

Hom.:

Cov.:

AF XY:

0.00768

AC XY:

572

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.0503

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00487

Gnomad4 OTH

AF:

0.00945

Alfa

AF:

0.00551

Hom.:

Bravo

AF:

0.0156

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.0188

AC:

2286

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2018	This variant is associated with the following publications: (PMID: 24037902, 23299917, 19035361, 27535533, 30847666) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 12, 2017	Variant summary: The TCAP c.316C>T (p.Arg106Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2260/116004 control chromosomes (178 homozygotes) at a frequency of 0.0194821, which is approximately 779 times the estimated maximal expected allele frequency of a pathogenic TCAP variant (0.000025), suggesting this variant is likely a benign polymorphism. The frequency of this variant is particularly higher in Latino populations (0.1744 in ExAC and 0.1526 in GnomAD). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. This variant was reported in HCM (n=1), DCM (n=2), and familial secundum-type atrial septal defect (n=1); however, causal role of the variant in none of the patients has been established. This variant was found in 2 cases where it was co-occurring with TNNI3 c.433C>T, p.Arg145Trp (pathogenic in our internal database) (Anderson_HM_2008) and 2 cases with sudden unexpected death in infancy, both in European (Danish) population. Taken together, this could be a functional polymorphism or modifier; therefore, this variant was classified as likely benign until further co-segregation and functional studies become available. -

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 03, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2015	p.Arg106Cys in exon 2 of TCAP: This variant is not expected to have clinical sig nificance because it has been identified in 17.4% (1953/11200) of Latino chromos omes, including 177 homozygotes, by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org/; dbSNP rs45578741). Of note, this variant was initia lly described as disease-causing based on its identification in 2 Caucasian indi viduals with HCM and absence from 400 healthy controls (Perrot 2006, Andersen 20 08). -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 16, 2015

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Arg106Cys variant in TCAP has been identified in at least 1 Danish individual with hypertrophic cardiomyopathy (PMID: 19035361). This variant is classified as benign for autosomal dominant hypertrophic cardiomyopathy because it has been identified in >17% of Latino chromosomes and 178 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). -

Primary familial hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2019

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Autosomal recessive limb-girdle muscular dystrophy type 2G

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0031

T;T

MetaSVM

Uncertain

0.011

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.35

MPC

1.0

ClinPred

0.029

GERP RS

5.7

Varity_R

0.50

gMVP

0.55

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