17-39665391-C-A

Position:

• chr17-39665391-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003673.4(TCAP):​c.32C>A​(p.Ser11Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCAP NM_003673.4 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.702

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-39665391-C-A is Pathogenic according to our data. Variant chr17-39665391-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140582.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-39665391-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4	c.32C>A	p.Ser11Ter	stop_gained	1/2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3	c.32C>A	p.Ser11Ter	stop_gained	1/2	1	NM_003673.4	ENSP00000312624	P1
TCAP	ENST00000578283.1	c.32C>A	p.Ser11Ter	stop_gained	1/3	5		ENSP00000462787

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2G Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Evolutionary and Medical Genetics Laboratory, Center for Cellular and Molecular Biology

Nov 04, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.20	N
MutationTaster	Benign	1.0	A;A
Vest4		0.42
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs45495192; hg19: chr17-37821644;