rs762850913

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP4

The NM_003673.4(TCAP):c.448G>A(p.Gly150Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,607,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G150D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

TCAP
NM_003673.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 6.65

Publications

4 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 23 uncertain in NM_003673.4

BP4

Computational evidence support a benign effect (MetaRNN=0.3042691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCAP	NM_003673.4 link	c.448G>A	p.Gly150Ser	missense_variant	Exon 2 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.448G>A	p.Gly150Ser	missense_variant	Exon 2 of 2	1	NM_003673.4	ENSP00000312624.2		O15273
TCAP	ENST00000578283.1 link	c.376G>A	p.Gly126Ser	missense_variant	Exon 3 of 3	5		ENSP00000462787.1		J3KT40

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000490

AC:

AN:

244758

AF XY:

0.0000601

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1455274

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

106

AN XY:

724264

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000172

AC:

191

AN:

1111906

Other (OTH)

AF:

0.000149

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000960

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jan 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in a patient with dilated cardiomyopathy; however, no further clinical or segregation information was provided (PMID: 31983221); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 31983221, 38002985) -

Jun 12, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TCAP-related disorder

Uncertain:1

Mar 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TCAP c.448G>A variant is predicted to result in the amino acid substitution p.Gly150Ser. This variant was reported in individuals with dilated cardiomyopathy or hypertrophic cardiomyopathy (online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666; Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant is reported in 0.0086% 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. -

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Apr 15, 2015

Blueprint Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Aug 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G150S variant (also known as c.448G>A), located in coding exon 2 of the TCAP gene, results from a G to A substitution at nucleotide position 448. The glycine at codon 150 is replaced by serine, an amino acid with similar properties. This variant was detected in cardiomyopathy genetic testing cohorts; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ventricular tachycardia

Uncertain:1

May 14, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25

Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 150 of the TCAP protein (p.Gly150Ser). This variant is present in population databases (rs762850913, gnomAD 0.009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 222831). 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

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.66

D;.

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.86

D;D

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.4

L;.

PhyloP100

6.7

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.8

N;.

REVEL

Uncertain

0.34

Sift

Benign

0.11

T;.

Sift4G

Benign

0.61

T;T

Polyphen

0.92

P;.

Vest4

0.27

MutPred

0.57

Gain of phosphorylation at G150 (P = 0.0187);.;

MVP

0.96

MPC

0.94

ClinPred

0.19

GERP RS

4.8

Varity_R

0.15

gMVP

0.35

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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