Variant X-117909589-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001168302.2(KLHL13):c.1030C>T(p.Arg344Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000207 in 1,209,835 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000018 ( 0 hom. 8 hem. )

Consequence

KLHL13
NM_001168302.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.55

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL13	NM_001168302.2 linkuse as main transcript	c.1030C>T	p.Arg344Cys	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.1030C>T	p.Arg344Cys	missense_variant	6/8	2	NM_001168302.2		Q9P2N7-3

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111686

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33878

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000940

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

182858

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67508

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1098149

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363509

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.0000214

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000448

AC:

AN:

111686

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33878

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000940

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.00000824

AC:

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

Aug 17, 2022

The c.1087C>T (p.R363C) 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 1087, causing the arginine (R) at amino acid position 363 to be replaced by a cysteine (C). 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

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.030

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

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.50

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

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.5

.;.;.;L;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.77

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

REVEL

Uncertain

0.39

Sift

Benign

0.083

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

Sift4G

Uncertain

0.040

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

Polyphen

0.99, 0.99, 1.0

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

Vest4

0.75

MutPred

0.56

.;.;.;Loss of MoRF binding (P = 0.0111);.;.;.;.;

MVP

0.95

ClinPred

0.34

GERP RS

3.9

Varity_R

0.34

gMVP

0.73

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