15-65077805-G-C

Variant names:

• chr15-65077805-G-C
• rs1064797021
• NM_001101362.3:c.990G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001101362.3(KBTBD13):​c.990G>C​(p.Trp330Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. W330R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KBTBD13 NM_001101362.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.66
• Publications: 0 publications found

Genes affected

KBTBD13 (HGNC:37227): (kelch repeat and BTB domain containing 13) The gene belongs to a family of genes encoding proteins containing a BTB domain and several kelch repeats. The BTB domain functions as a protein-protein interaction module, which includes an ability to self-associate or to interact with non-BTB domain-containing proteins. The kelch motif typically occurs in groups of five to seven repeats, and has been found in proteins with diverse functions. Known functions of these family members include transcription regulation, ion channel tetramerization and gating, protein ubiquitination or degradation, and cytoskeleton regulation. The exact function of this family member has yet to be determined. [provided by RefSeq, Jun 2010]

KBTBD13 Gene-Disease associations (from GenCC):

• nemaline myopathy 6

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101362.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	NM_001101362.3	MANE Select	c.990G>C	p.Trp330Cys	missense	Exon 1 of 1	NP_001094832.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	ENST00000432196.5	TSL:6 MANE Select	c.990G>C	p.Trp330Cys	missense	Exon 1 of 1	ENSP00000388723.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 6 Uncertain:1

May 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan with cysteine at codon 330 of the KBTBD13 protein (p.Trp330Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KBTBD13-related disease. ClinVar contains an entry for this variant (Variation ID: 424530). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 provided Uncertain:1

Mar 30, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The W330C variant in the KBTBD13 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The W330C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W330C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position in the Kelch 4 repeat that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret W330C as a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.71		Gain of catalytic residue at L331 (P = 0.0134)
MVP		0.78
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.95

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: rs1064797021; hg19: chr15-65370143;