22-20465260-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_032775.4(KLHL22):c.710C>A(p.Pro237His) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KLHL22 NM_032775.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37

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 2 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=0.31566563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL22	NM_032775.4	c.710C>A	p.Pro237His	missense_variant	4/7	ENST00000328879.9
LOC124905085	XR_007068014.1	n.132+4154G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL22	ENST00000328879.9	c.710C>A	p.Pro237His	missense_variant	4/7	1	NM_032775.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727148

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

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

Dec 26, 2023

The c.710C>A (p.P237H) alteration is located in exon 4 (coding exon 3) of the KLHL22 gene. This alteration results from a C to A substitution at nucleotide position 710, causing the proline (P) at amino acid position 237 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	Uncertain	0.39
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.026	D;.;.
Polyphen		0.92	P;.;.
Vest4		0.38
MutPred		0.54		Loss of catalytic residue at P237 (P = 0.0016);.;.;
MVP		0.34
MPC		0.76
ClinPred		0.78	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.24
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

LitVar

Other links and lift over

dbSNP: rs2053215750; hg19: chr22-20819547;