17-39665718-G-T

Position:

• chr17-39665718-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_003673.4(TCAP):​c.113G>T​(p.Cys38Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000982 in 1,609,304 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: TCAP NM_003673.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 2.98

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_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000101 (147/1457030) while in subpopulation MID AF= 0.0047 (26/5530). AF 95% confidence interval is 0.00329. There are 1 homozygotes in gnomad4_exome. There are 64 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCAP	NM_003673.4	c.113G>T	p.Cys38Phe	missense_variant, splice_region_variant	2/2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3	c.113G>T	p.Cys38Phe	missense_variant, splice_region_variant	2/2	1	NM_003673.4	ENSP00000312624.2
TCAP	ENST00000578283.1	c.113G>T	p.Cys38Phe	missense_variant, splice_region_variant	2/3	5		ENSP00000462787.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000108 AC: 26 AN: 239770 Hom.: 0 AF XY: 0.000107 AC XY: 14 AN XY: 130618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1457030 Hom.: 1 Cov.: 30 AF XY: 0.0000883 AC XY: 64 AN XY: 724478

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000918

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 06, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2023	Reported in published literature in a Middle Eastern child with suspected Duchenne's muscular dystrophy who also harbored additional cardiogenetic variants, including an in-frame deletion of DMD gene, and in an individual with HCM who also harbored additional cardiogenetic variants (PMID: 28482373, 32451364); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32451364, Schiava2022[paper], 37298070, 16490376, 28482373) -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2G;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 15, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 19, 2017	- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jan 13, 2020

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2023

The p.C38F variant (also known as c.113G>T), located in coding exon 2 of the TCAP gene, results from a G to T substitution at nucleotide position 113. The cysteine at codon 38 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported as homozygous in an individual with atypical cerebral palsy (Nejabat M et al. Front Pediatr, 2021 Sep;9:734946). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 25, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 38 of the TCAP protein (p.Cys38Phe). This variant is present in population databases (rs375310569, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32451364). ClinVar contains an entry for this variant (Variation ID: 202108). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 22, 2021

Variant summary: TCAP c.113G>T (p.Cys38Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 239770 control chromosomes. The observed variant frequency is approximately 4.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TCAP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.113G>T has been reported in the literature in at-least one individual affected with autosomal recessive hypertrophic cardiomyopathy attributed to a homozygous pathogenic variant in the TRIM63 gene (example, Salazar-Mendiguchia_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. The co-occurrence with other pathogenic variant mentioned above (TRIM63, p.Gln247*), provides supporting evidence for a benign role due to an alternate molecular basis of disease (Salazar-Mendiguchia_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. However, none of the submitters cite the evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Benign	0.85
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Uncertain	0.64
Sift	Benign	0.52	T;.
Sift4G	Benign	0.40	T;T
Polyphen		0.99	D;.
Vest4		0.30
MVP		0.97
MPC		1.2
ClinPred		0.37	T
GERP RS		5.7
Varity_R		0.57
gMVP		0.35

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: rs375310569; hg19: chr17-37821971;