17-39665921-C-T

Variant names:

• chr17-39665921-C-T
• rs45578741
• NM_003673.4:c.316C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003673.4(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (584 hom.)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 1.29

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]

ACMG classification

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 rank	MANE	Protein	UniProt
TCAP	NM_003673.4	c.316C>T	p.Arg106Cys	missense_variant	Exon 2 of 2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3	c.316C>T	p.Arg106Cys	missense_variant	Exon 2 of 2	1	NM_003673.4	ENSP00000312624.2
TCAP	ENST00000578283.1	c.244C>T	p.Arg82Cys	missense_variant	Exon 3 of 3	5		ENSP00000462787.1

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152216 Hom.: 36 Cov.: 32

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

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.: 31 AF XY: 0.00767 AC XY: 5574 AN XY: 726590

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.: 38 Cov.: 32 AF XY: 0.00768 AC XY: 572 AN XY: 74476

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.: 11

Bravo AF: 0.0156

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.0188 AC: 2286

Asia WGS AF: 0.00491 AC: 17 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

Submissions by phenotype

not provided Benign:8

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

not specified Benign:7

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). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 16, 2015

- -

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

- -

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/). -

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

Feb 02, 2025

- -

Autosomal recessive limb-girdle muscular dystrophy type 2G 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0031	T;T
MetaSVM	Uncertain	0.011	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.50	T
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	T
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

Other links and lift over

dbSNP: rs45578741; hg19: chr17-37822174; COSMIC: COSV54092899; COSMIC: COSV54092899;