rs756548785

Positions:

• chr17-39665383-C-G
• chr17-39665383-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003673.4(TCAP):​c.24C>G​(p.Cys8Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4	c.24C>G	p.Cys8Trp	missense_variant	1/2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3	c.24C>G	p.Cys8Trp	missense_variant	1/2	1	NM_003673.4	ENSP00000312624	P1
TCAP	ENST00000578283.1	c.24C>G	p.Cys8Trp	missense_variant	1/3	5		ENSP00000462787

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251038 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461472 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.7	D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.82		Gain of catalytic residue at L6 (P = 0.0036);Gain of catalytic residue at L6 (P = 0.0036);
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.90
gMVP		0.74

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

Other links and lift over

dbSNP: rs756548785; hg19: chr17-37821636;