Variant X-117909885-G-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.734C>G(p.Thr245Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,210,129 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 90 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 0.00091 ( 0 hom., 27 hem., cov: 24)

Exomes 𝑓: 0.00023 ( 0 hom. 63 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:

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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=0.020753354).

BS2

High Hemizygotes in GnomAd4 at 27 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL13	NM_001168302.2 linkuse as main transcript	c.734C>G	p.Thr245Ser	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.734C>G	p.Thr245Ser	missense_variant	6/8	2	NM_001168302.2		Q9P2N7-3

Frequencies

GnomAD3 genomes

AF:

0.000898

AC:

101

AN:

112411

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

34569

show subpopulations

Gnomad AFR

AF:

0.00288

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000377

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:

0.000131

Gnomad OTH

AF:

0.000665

GnomAD3 exomes

AF:

0.000459

AC:

AN:

183104

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

67658

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.000665

GnomAD4 exome

AF:

0.000233

AC:

256

AN:

1097664

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

363036

show subpopulations

Gnomad4 AFR exome

AF:

0.00364

Gnomad4 AMR exome

AF:

0.00102

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.000564

GnomAD4 genome

AF:

0.000907

AC:

102

AN:

112465

Hom.:

Cov.:

AF XY:

0.000780

AC XY:

AN XY:

34633

show subpopulations

Gnomad4 AFR

AF:

0.00290

Gnomad4 AMR

AF:

0.000376

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000131

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.00117

ESP6500AA

AF:

0.00313

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

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

Jul 28, 2021

The c.791C>G (p.T264S) alteration is located in exon 6 (coding exon 6) of the KLHL13 gene. This alteration results from a C to G substitution at nucleotide position 791, causing the threonine (T) at amino acid position 264 to be replaced by a serine (S). 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

0.21

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

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

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

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

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.021

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

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.42

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

MutationTaster

Benign

0.92

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

PrimateAI

Benign

0.46

PROVEAN

Benign

0.40

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

REVEL

Benign

0.27

Sift

Benign

0.032

D;D;D;T;T;T;T;.

Sift4G

Benign

0.13

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

Polyphen

0.0020, 0.0030, 0.056

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

Vest4

0.41

MutPred

0.63

.;.;.;Loss of ubiquitination at K259 (P = 0.2195);.;.;.;.;

MVP

0.59

ClinPred

0.041

GERP RS

4.9

Varity_R

0.26

gMVP

0.24

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