17-39666078-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_003673.4(TCAP):c.473G>T(p.Arg158Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R158C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.82

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-39666077-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44711.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=3, Likely_pathogenic=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCAP	NM_003673.4	c.473G>T	p.Arg158Leu	missense_variant	2/2	ENST00000309889.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCAP	ENST00000309889.3	c.473G>T	p.Arg158Leu	missense_variant	2/2	1	NM_003673.4	P1
TCAP	ENST00000578283.1	c.401G>T	p.Arg134Leu	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449862 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 721654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Apr 25, 2023

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 158 of the TCAP protein (p.Arg158Leu). 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. This variant disrupts the p.Arg158 amino acid residue in TCAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26084686, 27532257; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1004753). This variant has not been reported in the literature in individuals affected with TCAP-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	29
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.59		Loss of helix (P = 0.0123);.;
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.81
gMVP		0.52

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: rs397516864; hg19: chr17-37822331;