rs143233087

chr17-39665958-C-Achr17-39665958-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003673.4(TCAP):c.353C>A(p.Ala118Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A118V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22140479).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCAP	NM_003673.4	c.353C>A	p.Ala118Glu	missense_variant	2/2	ENST00000309889.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCAP	ENST00000309889.3	c.353C>A	p.Ala118Glu	missense_variant	2/2	1	NM_003673.4	P1
TCAP	ENST00000578283.1	c.281C>A	p.Ala94Glu	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2019

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"). This variant has not been reported in the literature in individuals with TCAP-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 118 of the TCAP protein (p.Ala118Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.82	N;.
REVEL	Uncertain	0.37
Sift	Benign	1.0	T;.
Sift4G	Benign	0.86	T;T
Polyphen		0.63	P;.
Vest4		0.13
MutPred		0.70		Gain of disorder (P = 0.0218);.;
MVP		0.95
MPC		1.0
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.34

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: rs143233087; hg19: chr17-37822211;