Variant 22-20489028-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_032775.4(KLHL22):c.184G>C(p.Glu62Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000774 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 0 hom. )

Consequence

KLHL22
NM_032775.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

Variant links:

Genes affected

KLHL22 (HGNC:25888): (kelch like family member 22) Enables 14-3-3 protein binding activity. Involved in several processes, including cellular protein metabolic process; cellular response to leucine; and mitotic spindle assembly checkpoint signaling. Located in several cellular components, including cytosol; intercellular bridge; and microtubule cytoskeleton. Part of Cul3-RING ubiquitin ligase complex. Colocalizes with lysosome and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

KLHL22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, KLHL22

BP4

Computational evidence support a benign effect (MetaRNN=0.025683165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL22	NM_032775.4 linkuse as main transcript	c.184G>C	p.Glu62Gln	missense_variant	2/7	ENST00000328879.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL22	ENST00000328879.9 linkuse as main transcript	c.184G>C	p.Glu62Gln	missense_variant	2/7	1	NM_032775.4	P1	Q53GT1-1

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000754

AC:

189

AN:

250808

Hom.:

AF XY:

0.000752

AC XY:

102

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00129

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000785

AC:

1148

AN:

1461732

Hom.:

Cov.:

AF XY:

0.000788

AC XY:

573

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000614

Gnomad4 FIN exome

AF:

0.0000939

Gnomad4 NFE exome

AF:

0.000915

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152306

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000820

Hom.:

Bravo

AF:

0.000650

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000865

AC:

105

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00154

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 18, 2022

The c.184G>C (p.E62Q) alteration is located in exon 2 (coding exon 1) of the KLHL22 gene. This alteration results from a G to C substitution at nucleotide position 184, causing the glutamic acid (E) at amino acid position 62 to be replaced by a glutamine (Q). 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

0.093

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;T;T;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

T;T;T;T;T;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.026

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.7

N;.;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.12

N;N;N;N;N;N

REVEL

Benign

0.054

Sift

Benign

0.29

T;T;T;T;T;T

Sift4G

Benign

0.45

T;.;T;.;.;.

Polyphen

0.060

B;.;.;.;.;.

Vest4

0.21

MVP

0.59

MPC

0.66

ClinPred

0.029

GERP RS

5.1

Varity_R

0.41

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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