chr22-20465035-G-T

Variant names:

• chr22-20465035-G-T
• rs774765494
• NM_032775.4:c.935C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032775.4(KLHL22):​c.935C>A​(p.Thr312Asn) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T312S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL22 NM_032775.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16129997).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032775.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL22	NM_032775.4	MANE Select	c.935C>A	p.Thr312Asn	missense	Exon 4 of 7	NP_116164.2
	KLHL22	NR_033825.2		n.838C>A		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL22	ENST00000328879.9	TSL:1 MANE Select	c.935C>A	p.Thr312Asn	missense	Exon 4 of 7	ENSP00000331682.4	Q53GT1-1
	KLHL22	ENST00000871932.1		c.935C>A	p.Thr312Asn	missense	Exon 4 of 7	ENSP00000541991.1
	KLHL22	ENST00000871933.1		c.935C>A	p.Thr312Asn	missense	Exon 4 of 7	ENSP00000541992.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T
Eigen	Benign	0.044
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.9
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.33	T
Polyphen		0.17	B
Vest4		0.32
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0249)
MVP		0.48
MPC		0.67
ClinPred		0.57	D
GERP RS		4.9
Varity_R		0.078
gMVP		0.34
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs774765494; hg19: chr22-20819322;