rs45458802

Positions:

chr17-39665796-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003673.4(TCAP):c.191C>T(p.Ser64Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000694 in 1,607,660 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S64S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 4 hom. )

Consequence

TCAP
NM_003673.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.33

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=0.019053161).

BP6

Variant 17-39665796-C-T is Benign according to our data. Variant chr17-39665796-C-T is described in ClinVar as [Benign]. Clinvar id is 44705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-39665796-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00389 (592/152296) while in subpopulation AFR AF= 0.0135 (563/41552). AF 95% confidence interval is 0.0126. There are 5 homozygotes in gnomad4. There are 274 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCAP	NM_003673.4 linkuse as main transcript	c.191C>T	p.Ser64Leu	missense_variant	2/2	ENST00000309889.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCAP	ENST00000309889.3 linkuse as main transcript	c.191C>T	p.Ser64Leu	missense_variant	2/2	1	NM_003673.4	P1
TCAP	ENST00000578283.1 linkuse as main transcript	c.174+17C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00389

AC:

592

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000805

AC:

192

AN:

238518

Hom.:

AF XY:

0.000617

AC XY:

AN XY:

129760

show subpopulations

Gnomad AFR exome

AF:

0.0117

Gnomad AMR exome

AF:

0.000269

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000339

Gnomad FIN exome

AF:

0.0000494

Gnomad NFE exome

AF:

0.0000281

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.000359

AC:

523

AN:

1455364

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

225

AN XY:

723478

show subpopulations

Gnomad4 AFR exome

AF:

0.0135

Gnomad4 AMR exome

AF:

0.000318

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000586

Gnomad4 FIN exome

AF:

0.0000385

Gnomad4 NFE exome

AF:

0.00000992

Gnomad4 OTH exome

AF:

0.000665

GnomAD4 genome

AF:

0.00389

AC:

592

AN:

152296

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

274

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0135

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00157

Hom.:

Bravo

AF:

0.00420

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000998

AC:

121

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	Ser64Leu in Exon 02 of TCAP: This variant is not expected to have clinical signi ficance because it has been identified in 1.2% (43/3730) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs45458802). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 14, 2014	- -

Hypertrophic cardiomyopathy;C0023976:Long QT syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 03, 2019

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 12, 2016

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2015

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. -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.019

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.41

Sift

Benign

0.070

Sift4G

Uncertain

0.037

Polyphen

0.74

Vest4

0.49

MVP

0.97

MPC

0.36

ClinPred

0.020

GERP RS

5.7

Varity_R

0.43

gMVP

0.60

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