17-39665813-C-T

Position:

chr17-39665813-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_003673.4(TCAP):c.208C>T(p.Arg70Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,606,332 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R70R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

TCAP
NM_003673.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:11

Conservation

PhyloP100: 1.94

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4 linkuse as main transcript	c.208C>T	p.Arg70Trp	missense_variant	2/2	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.208C>T	p.Arg70Trp	missense_variant	2/2	1	NM_003673.4	ENSP00000312624.2		O15273
TCAP	ENST00000578283.1 linkuse as main transcript	c.174+34C>T		intron_variant		5		ENSP00000462787.1		J3KT40

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000462

AC:

AN:

238314

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

129658

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000899

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000374

Gnomad OTH exome

AF:

0.000343

GnomAD4 exome

AF:

0.0000358

AC:

AN:

1454208

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

722592

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000910

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000352

Gnomad4 OTH exome

AF:

0.0000833

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 27, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Apr 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 15, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 25

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 29, 2006

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The p.R70W variant (also known as c.208C>T), located in coding exon 2 of the TCAP gene, results from a C to T substitution at nucleotide position 208. The arginine at codon 70 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in the homozygous state (along with other homozygous variants) in a patient with complex congenital heart defect, ambiguous genitalia, and mild limb hypotonia (Mazen I et al. Sex Dev, 2016 Apr;10:16-22). This variant has also been detected in the heterozygous state in cohorts with cardiomyopathy or arrhythmia (Theis JL et al. Biochem Biophys Res Commun, 2006 Dec;351:896-902; Blom LJ et al. Europace, 2019 Oct;21:1519-1526; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487; Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 70 of the TCAP protein (p.Arg70Trp). This variant is present in population databases (rs775636212, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy and/or dilated cardiomyopathy (PMID: 17097056, 32880476; Invitae). ClinVar contains an entry for this variant (Variation ID: 189789). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2G;C4225408:Hypertrophic cardiomyopathy 25

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.38

MVP

0.99

MPC

0.96

ClinPred

0.85

GERP RS

5.7

Varity_R

0.69

gMVP

0.72

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