Genetic Variant KBTBD13:p.Val224Leu (chr15-65077485-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001101362.3(KBTBD13):c.670G>T(p.Val224Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000146 in 1,371,992 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V224M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

KBTBD13
NM_001101362.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.71

Publications

0 publications found

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]

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

KBTBD13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KBTBD13	NM_001101362.3 link	c.670G>T	p.Val224Leu	missense_variant	Exon 1 of 1	ENST00000432196.5	NP_001094832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KBTBD13	ENST00000432196.5 link	c.670G>T	p.Val224Leu	missense_variant	Exon 1 of 1	6	NM_001101362.3	ENSP00000388723.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1371992

Hom.:

Cov.:

AF XY:

0.00000297

AC XY:

AN XY:

674406

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30902

American (AMR)

AF:

0.00

AC:

AN:

35570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24962

East Asian (EAS)

AF:

0.00

AC:

AN:

35280

South Asian (SAS)

AF:

0.00

AC:

AN:

78658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5210

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1070536

Other (OTH)

AF:

0.00

AC:

AN:

57168

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.062

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.7

PhyloP100

4.7

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.32

Sift

Uncertain

0.026

Sift4G

Benign

0.11

Polyphen

0.93

Vest4

0.48

MutPred

0.31

Loss of methylation at K222 (P = 0.1084);

MVP

0.63

MPC

1.1

ClinPred

0.74

GERP RS

3.8

Varity_R

0.19

gMVP

0.41

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over