Variant X-117919523-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001168302.2(KLHL13):c.520G>T(p.Gly174Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000369 in 1,082,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

KLHL13
NM_001168302.2 missense, splice_region

Scores

Splicing: ADA: 0.8609

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL13	NM_001168302.2 linkuse as main transcript	c.520G>T	p.Gly174Trp	missense_variant, splice_region_variant	5/8	ENST00000540167.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL13	ENST00000540167.6 linkuse as main transcript	c.520G>T	p.Gly174Trp	missense_variant, splice_region_variant	5/8	2	NM_001168302.2		Q9P2N7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000369

AC:

AN:

1082714

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

349908

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000362

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

May 09, 2023

The c.577G>T (p.G193W) alteration is located in exon 5 (coding exon 5) of the KLHL13 gene. This alteration results from a G to T substitution at nucleotide position 577, causing the glycine (G) at amino acid position 193 to be replaced by a tryptophan (W). 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

0.90

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

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

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.54

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

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

-0.60

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.6

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

REVEL

Uncertain

0.53

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.94, 0.94, 0.98

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

Vest4

0.65

MutPred

0.53

.;.;.;Loss of glycosylation at S189 (P = 0.0274);.;.;.;.;

MVP

0.86

ClinPred

0.92

GERP RS

4.9

Varity_R

0.40

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.86

dbscSNV1_RF

Benign

0.65

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over