rs193922920

chr16-29798640-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_007317.3(KIF22):c.442C>T(p.Pro148Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P148L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF22 NM_007317.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.18

Genes affected

KIF22 (HGNC:6391): (kinesin family member 22) The protein encoded by this gene is a member of the kinesin-like protein family. The family members are microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. The C-terminal half of this protein has been shown to bind DNA. Studies with the Xenopus homolog suggests its essential role in metaphase chromosome alignment and maintenance. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 15) in uniprot entity KIF22_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_007317.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-29798641-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 16-29798640-C-T is Pathogenic according to our data. Variant chr16-29798640-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30333.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-29798640-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF22	NM_007317.3	c.442C>T	p.Pro148Ser	missense_variant	4/14	ENST00000160827.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF22	ENST00000160827.9	c.442C>T	p.Pro148Ser	missense_variant	4/14	1	NM_007317.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 13, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 30333). This missense change has been observed in individuals with clinical features of spondyloepimetaphyseal dysplasia with joint laxity (PMID: 22152677; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 148 of the KIF22 protein (p.Pro148Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant disrupts the p.Pro148 amino acid residue in KIF22. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22152677, 22152678, 25256152). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Spondyloepimetaphyseal dysplasia with multiple dislocations Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 09, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.4	D;D;.;D;D
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Uncertain	0.030	D;D;T;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.82
MutPred		0.85		.;Gain of phosphorylation at P148 (P = 0.0768);.;.;.;
MVP		0.92
MPC		0.85
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.81
gMVP		0.82

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

Other links and lift over

dbSNP: rs193922920; hg19: chr16-29809961;