17-39665360-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003673.4(TCAP):c.1A>G(p.Met1?) variant causes a start lost 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCAP NM_003673.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.16

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-39665360-A-G is Pathogenic according to our data. Variant chr17-39665360-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587470.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCAP	NM_003673.4	c.1A>G	p.Met1?	start_lost	1/2	ENST00000309889.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCAP	ENST00000309889.3	c.1A>G	p.Met1?	start_lost	1/2	1	NM_003673.4	P1
TCAP	ENST00000578283.1	c.1A>G	p.Met1?	start_lost	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.53
Sift	Benign	0.22	T;.
Sift4G	Benign	0.080	T;T
Polyphen		0.15	B;.
Vest4		0.41
MutPred		0.55		Gain of catalytic residue at M1 (P = 0.0915);Gain of catalytic residue at M1 (P = 0.0915);
MVP		0.91
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1567864804; hg19: chr17-37821613;