17-39665874-C-T

Position:

chr17-39665874-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_003673.4(TCAP):c.269C>T(p.Pro90Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,611,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P90P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TCAP
NM_003673.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.20

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 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4 link	c.269C>T	p.Pro90Leu	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 link	c.269C>T	p.Pro90Leu	missense_variant	2/2	1	NM_003673.4	ENSP00000312624.2		O15273
TCAP	ENST00000578283.1 link	c.197C>T	p.Pro66Leu	missense_variant	3/3	5		ENSP00000462787.1		J3KT40

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000410

AC:

AN:

243776

Hom.:

AF XY:

0.00000752

AC XY:

AN XY:

132970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1459194

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

725840

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000302

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2011

The Pro90Leu variant has been reported in one individual with HCM and was absent from 400 control chromosomes (200 White, 200 Black; Bos 2006). Of note, this i ndividual also carried a MYBPC3 variant of possible significance (Gln998Arg). O ur laboratory has detected the Pro90Leu variant in 1 Caucasian DCM proband (out of >336 Caucasian probands tested). Proline (Pro) at position 90 is conserved a cross evolutionary distant species, suggesting that a change would not be tolera ted. However it is not conserved in a single mammalian species (chimp has an al anine), making it difficult to interpret this data. Three computer tools (Polyp hen2, SIFT, MAPP) predict this change to be deleterious; however, their accuracy is unknown. In summary, additional data (functional/segregation/control studies ) is needed to determine the clinical significance of this variant. -

TCAP-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2024

The TCAP c.269C>T variant is predicted to result in the amino acid substitution p.Pro90Leu. This variant has been reported in one patient with hypertrophic cardiomyopathy (HCM), who was also heterozygous for a missense variant in a different HCM-related gene (Bos et al. 2006. PubMed ID: 16352453). This variant was also found in a patient with dilated cardiomyopathy (DCM) and was reported as a variant of uncertain significance (Table S1B, Walsh et al. 2017. PubMed ID: 27532257). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 21, 2020

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2024

The p.P90L variant (also known as c.269C>T), located in coding exon 2 of the TCAP gene, results from a C to T substitution at nucleotide position 269. The proline at codon 90 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant 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

Sep 21, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 177970). This missense change has been observed in individual(s) with either hypertrophic cardiomyopathy (HCM) and/or dilated cardiomyopathy (DCM) (PMID: 16352453, 27532257). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 90 of the TCAP protein (p.Pro90Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;T

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-8.3

D;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0070

D;.

Sift4G

Uncertain

0.025

D;D

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.70

Loss of loop (P = 0.0022);.;

MVP

0.99

MPC

0.76

ClinPred

1.0

GERP RS

5.7

Varity_R

0.61

gMVP

0.62

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