Variant 22-20442311-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032775.4(KLHL22):c.1667G>A(p.Arg556His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KLHL22
NM_032775.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.92

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:

LOC107985588 (HGNC:):

LOC107985588 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17151177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL22	NM_032775.4 linkuse as main transcript	c.1667G>A	p.Arg556His	missense_variant	7/7	ENST00000328879.9	NP_116164.2
LOC107985588	XR_001755623.2 linkuse as main transcript	n.517-513C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL22	ENST00000328879.9 linkuse as main transcript	c.1667G>A	p.Arg556His	missense_variant	7/7	1	NM_032775.4	ENSP00000331682	P1	Q53GT1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250890

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727122

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

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

Dec 28, 2022

The c.1667G>A (p.R556H) alteration is located in exon 7 (coding exon 6) of the KLHL22 gene. This alteration results from a G to A substitution at nucleotide position 1667, causing the arginine (R) at amino acid position 556 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.037

MetaRNN

Benign

0.17

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.84

REVEL

Benign

0.28

Sift

Benign

0.15

Sift4G

Benign

0.18

Polyphen

0.99

Vest4

0.13

MutPred

0.36

Loss of MoRF binding (P = 0.0088);

MVP

0.60

MPC

0.79

ClinPred

0.49

GERP RS

5.7

Varity_R

0.043

gMVP

0.43

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