Variant X-117909774-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001168302.2(KLHL13):c.845C>T(p.Thr282Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,208,679 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000049 ( 0 hom. 24 hem. )

Consequence

KLHL13
NM_001168302.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

KLHL13 (HGNC:22931): (kelch like family member 13) This gene encodes a BTB and kelch domain containing protein and belongs to the kelch repeat domain containing superfamily of proteins. The encoded protein functions as an adaptor protein that complexes with Cullin 3 and other proteins to form the Cullin 3-based E3 ubiquitin-protein ligase complex. This complex is necessary for proper chromosome segregation and completion of cytokinesis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

KLHL13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21485934).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL13	NM_001168302.2 linkuse as main transcript	c.845C>T	p.Thr282Met	missense_variant	6/8	ENST00000540167.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL13	ENST00000540167.6 linkuse as main transcript	c.845C>T	p.Thr282Met	missense_variant	6/8	2	NM_001168302.2		Q9P2N7-3

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111872

Hom.:

Cov.:

AF XY:

0.0000877

AC XY:

AN XY:

34206

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00114

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

183132

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

67696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000492

AC:

AN:

1096755

Hom.:

Cov.:

AF XY:

0.0000663

AC XY:

AN XY:

362249

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000995

Gnomad4 SAS exome

AF:

0.000462

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000250

Gnomad4 OTH exome

AF:

0.0000869

GnomAD4 genome

AF:

0.0000447

AC:

AN:

111924

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34270

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00114

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Jan 31, 2022

The c.902C>T (p.T301M) alteration is located in exon 6 (coding exon 6) of the KLHL13 gene. This alteration results from a C to T substitution at nucleotide position 902, causing the threonine (T) at amino acid position 301 to be replaced by a methionine (M). 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

Uncertain

0.38

BayesDel_addAF

Benign

0.0052

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

.;.;.;T;.;.;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;.;D;D;D;.;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.0

.;.;.;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.018

D;D;D;D;D;D;D;.

Sift4G

Benign

0.092

T;T;T;T;T;T;T;.

Polyphen

0.90, 0.94, 1.0

.;.;.;P;.;P;P;D

Vest4

0.62

MVP

0.71

ClinPred

0.18

GERP RS

4.9

Varity_R

0.30

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

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