chr17-39665918-G-C

Position:

chr17-39665918-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003673.4(TCAP):c.313G>C(p.Glu105Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0011 in 1,612,906 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

TCAP
NM_003673.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:8

Conservation

PhyloP100: 3.73

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051429212).

BP6

Variant 17-39665918-G-C is Benign according to our data. Variant chr17-39665918-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191776.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=9}. Variant chr17-39665918-G-C is described in Lovd as [Likely_benign]. Variant chr17-39665918-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000676 (103/152332) while in subpopulation AMR AF= 0.00209 (32/15306). AF 95% confidence interval is 0.00152. There are 1 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4 linkuse as main transcript	c.313G>C	p.Glu105Gln	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.313G>C	p.Glu105Gln	missense_variant	2/2	1	NM_003673.4	ENSP00000312624.2		O15273
TCAP	ENST00000578283.1 linkuse as main transcript	c.241G>C	p.Glu81Gln	missense_variant	3/3	5		ENSP00000462787.1		J3KT40

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

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:

0.000911

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000510

AC:

127

AN:

248982

Hom.:

AF XY:

0.000525

AC XY:

AN XY:

135172

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000899

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:

0.000794

Gnomad OTH exome

AF:

0.000821

GnomAD4 exome

AF:

0.00115

AC:

1676

AN:

1460574

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

787

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.00138

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152332

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000911

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000648

Hom.:

Bravo

AF:

0.000812

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	This variant is associated with the following publications: (PMID: 31303467, 24037902, 23861362, 30871747) -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TCAP: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2023	- -

not specified

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 23, 2015	The p.Glu105Gln variant in TCAP has not been previously reported in individuals with cardiomyopathy, but has been identified in 36/62742 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s146906267). Computational prediction tools and conservation analysis suggest th at this variant may not impact the protein, though this information is not predi ctive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu105Gln variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2023	Variant summary: TCAP c.313G>C (p.Glu105Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 248982 control chromosomes. The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in TCAP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.313G>C has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (example, Earle_2015), as a VUS with non-informative segregation along with a VUS in TNNT2 gene in an individual with dilated cardiomyopathy (example, Sousa_2019) and identified once in a whole exome sequencing study with participants who were not pre-selected for a personal or family history of arrhythmia, cardiomyopathy or sudden cardiac death (example, Ng_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23861362, 26332198, 30871747). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4, VUS, n=9). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 22, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu105Gln (c.313 G>C, E105Q) in the TCAP gene (NM_003673.3) TCAP encodes telethonin, which is a component of the z-disc. Variants in TCAP have been reported with cardiomyopathy, though the evidence that they cause cardiomyopathy is fairly weak. Using a candidate gene approach, Hayashi et al (2004) sequenced TCAP in a cohort of 346 HCM patients and 146 DCM patients from Asia. They found two different missense variants in two different families with HCM and in each family the variant was present in two affected first degree relatives (note that one of these variants is present in 2 of 6500 individuals in NHLBI ESP). They found another missense variant in a patient with DCM. The variant was inherited from his unaffected father, not his mother, who had HCM. Again with a candidate gene approach, Mike Ackerman's group sequenced z-disc genes and found three novel TCAP variants in 4 of 398 patients with HCM in their Mayo cohort. This included two missense variants and one in-frame single amino acid deletion.Variants in this gene have also been reported with limb girdle muscular dystrophy (Moreira et al 2000). Reviewing the NHLBI ESP exome variant server, 8 of ~6500 (0.1%) individuals have a rare missense variant (present in 1-3 individuals). We consider it a variant of uncertain significance, given the lack of case data, the weak gene level evidence, and the presence in general population samples. The variant appears to be novel. Polyphen predicts the variant to be possibly damaging. The glutamate at codon 105 is highly, though not completely, conserved across species, as are neighboring amino acids. The Grantham score is 29. Another variant at the same codon (p.Glu105Lys) was reported in one individual in a French Canadian cohort of 96 individuals with DCM (Hirtle-Lewis et al 2013). In total, the variant has been seen in 7 of 7972 individuals from publicly available datasets. The variant was reported online in 5 of 4295 Caucasian individuals and 1 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of April 22nd, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Per the GeneDx report, it is also present at low frequency in the 1000 genomes dataset. The ClinSeq group reported that they observed the variant in 1 of 1474 individuals (Ng et al 2013). The variant is listed in dbSNP (rs146906267), with reference to the NHLBI ESP, 1000 genomes, and ClinSeq data -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Apr 19, 2017

- -

Hypertrophic cardiomyopathy 25

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 105 of the TCAP protein (p.Glu105Gln). This variant is present in population databases (rs146906267, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy and hypertrophic cardiomyopathy (PMID: 24037902, 26332198, 30871747, 31303467). ClinVar contains an entry for this variant (Variation ID: 191776). 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 13, 2019

- -

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 24, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2020

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.2

N;.

REVEL

Uncertain

0.44

Sift

Benign

0.20

T;.

Sift4G

Benign

0.20

T;T

Polyphen

0.89

P;.

Vest4

0.12

MVP

0.94

MPC

0.66

ClinPred

0.036

GERP RS

4.7

Varity_R

0.14

gMVP

0.31

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