15-69416058-G-A

Variant names:

• chr15-69416058-G-A
• rs139012996
• NM_001367805.3:c.76G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001367805.3(KIF23):​c.76G>A​(p.Val26Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000255 in 1,572,286 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: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: KIF23 NM_001367805.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

Genes affected

KIF23 (HGNC:6392): (kinesin family member 23) The protein encoded by this gene is a member of kinesin-like protein family. This family includes microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. This protein has been shown to cross-bridge antiparallel microtubules and drive microtubule movement in vitro. Alternate splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2615913).
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF23	NM_001367805.3	c.76G>A	p.Val26Ile	missense_variant	Exon 2 of 24	ENST00000679126.1	NP_001354734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF23	ENST00000679126.1	c.76G>A	p.Val26Ile	missense_variant	Exon 2 of 24		NM_001367805.3	ENSP00000504770.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000353

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000139 AC: 30 AN: 215310 Hom.: 0 AF XY: 0.000136 AC XY: 16 AN XY: 117848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000241

Gnomad OTH exome AF: 0.000402

GnomAD4 exome AF: 0.000263 AC: 374 AN: 1419942 Hom.: 0 Cov.: 28 AF XY: 0.000238 AC XY: 168 AN XY: 705996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000153

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000328

Gnomad4 OTH exome AF: 0.000136

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74504

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 26 of the KIF23 protein (p.Val26Ile). This variant is present in population databases (rs139012996, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KIF23-related conditions. ClinVar contains an entry for this variant (Variation ID: 2175905). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KIF23 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.3	L;.;L;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.69	N;N;N;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.049	D;D;D;.;D
Sift4G	Uncertain	0.056	T;T;T;.;T
Polyphen		1.0	D;.;D;D;.
Vest4		0.42
MVP		0.67
MPC		0.30
ClinPred		0.18	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.13

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: rs139012996; hg19: chr15-69708397;