rs397516865

Positions:

• chr17-39666098-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003673.4(TCAP):​c.493C>G​(p.Gln165Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4	c.493C>G	p.Gln165Glu	missense_variant	2/2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3	c.493C>G	p.Gln165Glu	missense_variant	2/2	1	NM_003673.4	ENSP00000312624.2
TCAP	ENST00000578283.1	c.421C>G	p.Gln141Glu	missense_variant	3/3	5		ENSP00000462787.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 01, 2012

The Gln165Glu variant in TCAP has not been reported in the literature, but has b een identified in 1 individual with DCM as well as 3 affected relatives. This va riant has not been identified in a very large and broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), which is consistent with a pathogenic role. Computational analyses (biochemical amino acid properti es, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Heterozygous TCAP variants have been de tected in patients with HCM, as well as DCM (Hayashi 2004, Bos 2006), but the ro le of TCAP in these disorders is still incompletely characterized. Homozygous TC AP variants have been associated with limb girdle muscular dystrophy (LGMD2G). Additional evidence is needed to determine its clinical significance. -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 44713). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257, 31983221). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 165 of the TCAP protein (p.Gln165Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Uncertain	0.71	D;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D;.
Sift4G	Benign	0.066	T;T
Polyphen		1.0	D;.
Vest4		0.51
MutPred		0.37		Loss of MoRF binding (P = 0.0591);.;
MVP		0.93
MPC		0.97
ClinPred		0.87	D
GERP RS		5.8
Varity_R		0.34
gMVP		0.42

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

Other links and lift over

dbSNP: rs397516865; hg19: chr17-37822351;