Variant X-117898954-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001168302.2(KLHL13):c.1874A>G(p.Glu625Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000117 in 1,209,020 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 0 hom. 40 hem. )

Consequence

KLHL13
NM_001168302.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.78

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:

KLHL13 (HGNC:):

KLHL13 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049581915).

BS2

High Hemizygotes in GnomAdExome4 at 40 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL13	NM_001168302.2 linkuse as main transcript	c.1874A>G	p.Glu625Gly	missense_variant	8/8	ENST00000540167.6	NP_001161774.1	Q9P2N7-3Q96HC9B7ZB44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL13	ENST00000540167.6 linkuse as main transcript	c.1874A>G	p.Glu625Gly	missense_variant	8/8	2	NM_001168302.2	ENSP00000441029.1		Q9P2N7-3

Frequencies

GnomAD3 genomes

AF:

0.0000980

AC:

AN:

112191

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34389

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000944

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:

0.000169

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000824

AC:

AN:

182028

Hom.:

AF XY:

0.0000599

AC XY:

AN XY:

66730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000733

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:

0.000160

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

130

AN:

1096780

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

362384

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000569

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:

0.000149

Gnomad4 OTH exome

AF:

0.0000652

GnomAD4 genome

AF:

0.0000980

AC:

AN:

112240

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34448

show subpopulations

Gnomad4 AFR

AF:

0.0000323

Gnomad4 AMR

AF:

0.0000943

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000169

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000906

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

Apr 22, 2024

The c.1931A>G (p.E644G) alteration is located in exon 8 (coding exon 8) of the KLHL13 gene. This alteration results from a A to G substitution at nucleotide position 1931, causing the glutamic acid (E) at amino acid position 644 to be replaced by a glycine (G). 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

0.090

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

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

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

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

M_CAP

Benign

0.066

MetaRNN

Benign

0.050

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

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.81

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

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.090

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

REVEL

Benign

0.087

Sift

Benign

0.29

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

Sift4G

Benign

0.44

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

Polyphen

0.12, 0.45, 0.29

.;.;.;B;.;B;B;B

Vest4

0.25

MVP

0.34

ClinPred

0.12

GERP RS

5.3

Varity_R

0.15

gMVP

0.26

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