rs755539784

Variant summary

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

The ENST00000309889.3(TCAP):​c.460C>A​(p.Arg154Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R154C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TCAP
ENST00000309889.3 missense

Scores

12
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.24
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
TCAPNM_003673.4 linkuse as main transcriptc.460C>A p.Arg154Ser 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.460C>A p.Arg154Ser missense_variant 2/21 NM_003673.4 ENSP00000312624 P1
TCAPENST00000578283.1 linkuse as main transcriptc.388C>A p.Arg130Ser missense_variant 3/35 ENSP00000462787

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 21, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 27, 2017- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 15, 2023The c.460C>A (p.R154S) alteration is located in exon 2 (coding exon 2) of the TCAP gene. This alteration results from a C to A substitution at nucleotide position 460, causing the arginine (R) at amino acid position 154 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
24
DANN
Benign
0.92
DEOGEN2
Uncertain
0.68
D;.
Eigen
Benign
-0.090
Eigen_PC
Benign
0.098
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.65
T;T
M_CAP
Uncertain
0.20
D
MetaRNN
Uncertain
0.44
T;T
MetaSVM
Benign
-0.29
T
MutationAssessor
Uncertain
2.0
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.4
N;.
REVEL
Uncertain
0.43
Sift
Uncertain
0.0090
D;.
Sift4G
Uncertain
0.013
D;D
Polyphen
0.12
B;.
Vest4
0.22
MutPred
0.60
Gain of phosphorylation at R154 (P = 0.0147);.;
MVP
0.97
MPC
0.63
ClinPred
0.82
D
GERP RS
5.8
Varity_R
0.28
gMVP
0.51

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: rs755539784; hg19: chr17-37822318; API