17-39665993-C-A

Variant names:

• chr17-39665993-C-A
• rs374886575
• NM_003673.4:c.388C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_003673.4(TCAP):​c.388C>A​(p.Arg130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,302 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R130H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.88
• Publications: 3 publications found

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]

TCAP Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 25

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2G

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003673.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCAP	NM_003673.4	MANE Select	c.388C>A	p.Arg130Ser	missense	Exon 2 of 2	NP_003664.1	A2TDC0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCAP	ENST00000309889.3	TSL:1 MANE Select	c.388C>A	p.Arg130Ser	missense	Exon 2 of 2	ENSP00000312624.2	O15273
	TCAP	ENST00000578283.1	TSL:5	c.316C>A	p.Arg106Ser	missense	Exon 3 of 3	ENSP00000462787.1	J3KT40

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460302 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726482

African (AFR) AF: 0.000358 AC: 12 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Benign	1.9	M
PhyloP100		1.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.014	D
Polyphen		0.98	D
Vest4		0.49
MutPred		0.75		Loss of catalytic residue at R130 (P = 0.0655)
MVP		0.96
MPC		1.0
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.84
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs374886575; hg19: chr17-37822246;