22-20465137-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_032775.4(KLHL22):c.833G>T(p.Arg278Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL22 NM_032775.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.650

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]

LOC124905085 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. 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=0.105962604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL22	NM_032775.4	c.833G>T	p.Arg278Leu	missense_variant	4/7	ENST00000328879.9
LOC124905085	XR_007068014.1	n.132+4031C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL22	ENST00000328879.9	c.833G>T	p.Arg278Leu	missense_variant	4/7	1	NM_032775.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.833G>T (p.R278L) alteration is located in exon 4 (coding exon 3) of the KLHL22 gene. This alteration results from a G to T substitution at nucleotide position 833, causing the arginine (R) at amino acid position 278 to be replaced by a leucine (L). 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	0.18
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	8.4
Dann	Uncertain	0.98
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.12	N;.
MutationTaster	Benign	0.90	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.68	N;N
REVEL	Benign	0.14
Sift	Benign	0.20	T;T
Sift4G	Benign	0.082	T;.
Polyphen		0.039	B;.
Vest4		0.43
MutPred		0.39		Loss of disorder (P = 0.0434);.;
MVP		0.49
MPC		0.73
ClinPred		0.19	T
GERP RS		0.59
Varity_R		0.061
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-20819424;