17-39665391-C-G

Variant names:

• chr17-39665391-C-G
• rs45495192
• NM_003673.4:c.32C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_003673.4(TCAP):​c.32C>G​(p.Ser11Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. S11L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.702
• Publications: 8 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37507594).

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.32C>G	p.Ser11Trp	missense	Exon 1 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.32C>G	p.Ser11Trp	missense	Exon 1 of 2	ENSP00000312624.2	O15273
	TCAP	ENST00000578283.1	TSL:5	c.32C>G	p.Ser11Trp	missense	Exon 1 of 3	ENSP00000462787.1	J3KT40

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251088 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461508 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727070

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111962

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.00060	D
MutationAssessor	Benign	1.9	M
PhyloP100		0.70
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.022	D
Polyphen		0.97	D
Vest4		0.37
MutPred		0.52		Loss of loop (P = 9e-04)
MVP		0.98
MPC		1.1
ClinPred		0.96	D
GERP RS		4.5
PromoterAI		-0.085	Neutral
Varity_R		0.38
gMVP		0.33
Mutation Taster		=68/32	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: rs45495192; hg19: chr17-37821644;