17-39665393-G-C

Variant names:

• chr17-39665393-G-C
• NM_003673.4:c.34G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003673.4(TCAP):​c.34G>C​(p.Glu12Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,996 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • 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: 5.92

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCAP	NM_003673.4	c.34G>C	p.Glu12Gln	missense_variant	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.34G>C	p.Glu12Gln	missense_variant	Exon 1 of 2	1	NM_003673.4	ENSP00000312624.2
TCAP	ENST00000578283.1	c.34G>C	p.Glu12Gln	missense_variant	Exon 1 of 3	5		ENSP00000462787.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457996 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 12 of the TCAP protein (p.Glu12Gln). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.52
MutPred		0.66		Loss of glycosylation at S11 (P = 0.0946);Loss of glycosylation at S11 (P = 0.0946);
MVP		0.95
MPC		0.94
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr17-37821646;