rs886038534

Positions:

• chr17-39665954-C-A
• chr17-39665954-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003673.4(TCAP):​c.349C>A​(p.Leu117Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L117L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30847704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCAP	NM_003673.4	c.349C>A	p.Leu117Met	missense_variant	2/2	ENST00000309889.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCAP	ENST00000309889.3	c.349C>A	p.Leu117Met	missense_variant	2/2	1	NM_003673.4	P1
TCAP	ENST00000578283.1	c.277C>A	p.Leu93Met	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0048	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.0036
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.62	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	-0.026	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.55	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.12	N;.
REVEL	Uncertain	0.33
Sift	Benign	0.30	T;.
Sift4G	Benign	0.26	T;T
Polyphen		0.68	P;.
Vest4		0.12
MutPred		0.72		Gain of disorder (P = 0.1057);.;
MVP		0.88
MPC		0.93
ClinPred		0.38	T
GERP RS		5.7
Varity_R		0.18
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-37822207;