17-39665391-C-CGGAGGAGAACTGTGA

Variant names:

• chr17-39665391-C-CGGAGGAGAACTGTGA
• NM_003673.4:c.34_48dupGAGGAGAACTGTGAG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_003673.4(TCAP):​c.34_48dupGAGGAGAACTGTGAG​(p.Glu12_Glu16dup) variant causes a conservative inframe insertion 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCAP NM_003673.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.58

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003673.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCAP	NM_003673.4	c.34_48dupGAGGAGAACTGTGAG	p.Glu12_Glu16dup	conservative_inframe_insertion	Exon 1 of 2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3	c.34_48dupGAGGAGAACTGTGAG	p.Glu12_Glu16dup	conservative_inframe_insertion	Exon 1 of 2	1	NM_003673.4	ENSP00000312624.2
TCAP	ENST00000578283.1	c.34_48dupGAGGAGAACTGTGAG	p.Glu12_Glu16dup	conservative_inframe_insertion	Exon 1 of 3	5		ENSP00000462787.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

May 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34_48dup15 variant (also known as p.E12_E16dup), located in coding exon 1 of the TCAP gene, results from an in-frame duplication of 15 nucleotides at nucleotide positions 34 to 48. This results in the duplication of 5 extra residues (EENCE) between codons 12 and 16. These amino acid positions range from highly conserved to poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.34_48dup, results in the insertion of 5 amino acid(s) of the TCAP protein (p.Glu12_Glu16dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). 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: 2146004). 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

Splicing

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: chr17-37821644;