Variant 3-67003703-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032505.3(KBTBD8):c.736G>A(p.Glu246Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

KBTBD8
NM_032505.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.87

Variant links:

Genes affected

KBTBD8 (HGNC:30691): (kelch repeat and BTB domain containing 8) Involved in neural crest cell development; neural crest formation; and protein monoubiquitination. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

KBTBD8 links:

KBTBD8 (HGNC:):

KBTBD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30735272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD8	NM_032505.3 linkuse as main transcript	c.736G>A	p.Glu246Lys	missense_variant	3/4	ENST00000417314.2	NP_115894.2	Q8NFY9-1
KBTBD8	XM_005264771.4 linkuse as main transcript	c.505G>A	p.Glu169Lys	missense_variant	2/3		XP_005264828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KBTBD8	ENST00000417314.2 linkuse as main transcript	c.736G>A	p.Glu246Lys	missense_variant	3/4	2	NM_032505.3	ENSP00000401878.2	Q8NFY9-1
KBTBD8	ENST00000460576.5 linkuse as main transcript	c.17-4219G>A		intron_variant		2		ENSP00000419738.1	Q8NFY9-2
KBTBD8	ENST00000469661.1 linkuse as main transcript	n.442G>A		non_coding_transcript_exon_variant	3/3	5
KBTBD8	ENST00000484414.5 linkuse as main transcript	c.*6G>A		downstream_gene_variant		3		ENSP00000417341.1	C9J331

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000797

AC:

AN:

250940

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000168

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000958

AC:

140

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.736G>A (p.E246K) alteration is located in exon 3 (coding exon 3) of the KBTBD8 gene. This alteration results from a G to A substitution at nucleotide position 736, causing the glutamic acid (E) at amino acid position 246 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.030

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.73

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.42

REVEL

Benign

0.28

Sift

Benign

0.18

Sift4G

Uncertain

0.026

Polyphen

0.64

Vest4

0.51

MVP

0.76

MPC

0.36

ClinPred

0.11

GERP RS

4.8

Varity_R

0.24

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over