rs45578741

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The ENST00000309889.3(TCAP):​c.316C>A​(p.Arg106Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,486 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R106C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TCAP
ENST00000309889.3 missense

Scores

1
13
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-39665921-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TCAPNM_003673.4 linkuse as main transcriptc.316C>A p.Arg106Ser missense_variant 2/2 ENST00000309889.3 NP_003664.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TCAPENST00000309889.3 linkuse as main transcriptc.316C>A p.Arg106Ser missense_variant 2/21 NM_003673.4 ENSP00000312624 P1
TCAPENST00000578283.1 linkuse as main transcriptc.244C>A p.Arg82Ser missense_variant 3/35 ENSP00000462787

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248892
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135182
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000892
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1460486
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726590
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 01, 2023This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 106 of the TCAP protein (p.Arg106Ser). This variant is present in population databases (rs45578741, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TCAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 566074). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
22
DANN
Benign
0.88
DEOGEN2
Pathogenic
0.86
D;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.78
T;T
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.49
T;T
MetaSVM
Uncertain
0.40
D
MutationAssessor
Uncertain
2.2
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-4.3
D;.
REVEL
Uncertain
0.59
Sift
Uncertain
0.020
D;.
Sift4G
Uncertain
0.014
D;D
Polyphen
0.98
D;.
Vest4
0.31
MutPred
0.58
Loss of helix (P = 0.0237);.;
MVP
0.97
MPC
0.63
ClinPred
0.97
D
GERP RS
5.7
Varity_R
0.63
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.

Other links and lift over

dbSNP: rs45578741; hg19: chr17-37822174; API