rs1303411209

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001101362.3(KBTBD13):​c.244G>A​(p.Val82Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000441 in 1,359,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

KBTBD13
NM_001101362.3 missense

Scores

1
10
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 4.95
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KBTBD13NM_001101362.3 linkc.244G>A p.Val82Met missense_variant Exon 1 of 1 ENST00000432196.5 NP_001094832.1 C9JR72

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KBTBD13ENST00000432196.5 linkc.244G>A p.Val82Met missense_variant Exon 1 of 1 6 NM_001101362.3 ENSP00000388723.2 C9JR72

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000441
AC:
6
AN:
1359662
Hom.:
0
Cov.:
58
AF XY:
0.00000298
AC XY:
2
AN XY:
670754
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000292
Gnomad4 SAS exome
AF:
0.0000393
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000188
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Nemaline myopathy 6 Pathogenic:1Uncertain:1
May 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 82 of the KBTBD13 protein (p.Val82Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KBTBD13-related conditions. ClinVar contains an entry for this variant (Variation ID: 435545). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KBTBD13 protein function with a negative predictive value of 80%. 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. -

Oct 08, 2018
NeuroMeGen, Hospital Clinico Santiago de Compostela
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Oct 13, 2016
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
May 02, 2019
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.045
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.92
D
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.67
D
MetaSVM
Uncertain
-0.095
T
MutationAssessor
Benign
1.7
L
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.6
N
REVEL
Benign
0.20
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.010
D
Polyphen
1.0
D
Vest4
0.50
MutPred
0.43
Gain of catalytic residue at V82 (P = 0.0165);
MVP
0.69
MPC
1.5
ClinPred
0.77
D
GERP RS
3.7
Varity_R
0.27
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1303411209; hg19: chr15-65369397; API