Genetic Variant KBTBD13:p.Pro91Leu (chr15-65077087-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001101362.3(KBTBD13):c.272C>T(p.Pro91Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,369,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. P91Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

KBTBD13
NM_001101362.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.21

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2926216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KBTBD13	NM_001101362.3 link	c.272C>T	p.Pro91Leu	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
KBTBD13	ENST00000432196.5 link	c.272C>T	p.Pro91Leu	missense_variant	Exon 1 of 1	6	NM_001101362.3	ENSP00000388723.2		C9JR72

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000840

AC:

AN:

119004

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000439

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:

0.00000219

AC:

AN:

1369128

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

675698

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29242

American (AMR)

AF:

0.0000293

AC:

AN:

34104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24470

East Asian (EAS)

AF:

0.0000292

AC:

AN:

34292

South Asian (SAS)

AF:

0.00

AC:

AN:

77464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5526

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1070724

Other (OTH)

AF:

0.00

AC:

AN:

56884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

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

Benign

0.18

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.24

Eigen

Benign

-0.047

Eigen_PC

Benign

-0.064

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

PhyloP100

2.2

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.11

Sift

Benign

0.14

Sift4G

Benign

0.23

Polyphen

0.87

Vest4

0.14

MutPred

0.45

Gain of helix (P = 0.0128);

MVP

0.64

MPC

1.1

ClinPred

0.73

GERP RS

3.5

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.16

gMVP

0.47

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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15-65077087-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over