dbSNP rs121908163: KIF1B:p.Pro1263Thr (chr1-10345943-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_001365951.3(KIF1B):c.3787C>A(p.Pro1263Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P1263S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KIF1B
NM_001365951.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.11

Variant links:

Genes affected

KIF1B (HGNC:16636): (kinesin family member 1B) Predicted to enable microtubule binding activity and plus-end-directed microtubule motor activity. Predicted to be involved in chemical synaptic transmission; dense core granule cytoskeletal transport; and vesicle-mediated transport. Predicted to act upstream of or within mitochondrion transport along microtubule. Predicted to be located in cytoplasmic vesicle membrane and neuron projection. Predicted to be part of kinesin complex. Predicted to be active in several cellular components, including axon; dendrite; and microtubule. Implicated in Charcot-Marie-Tooth disease type 2A1; carcinoma (multiple); multiple sclerosis; neuroblastoma; and pheochromocytoma. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

KIF1B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-10345943-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.26176488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1B	NM_001365951.3 link	c.3787C>A	p.Pro1263Thr	missense_variant	Exon 35 of 49	ENST00000676179.1	NP_001352880.1
KIF1B	NM_001365952.1 link	c.3787C>A	p.Pro1263Thr	missense_variant	Exon 35 of 49		NP_001352881.1
KIF1B	NM_015074.3 link	c.3649C>A	p.Pro1217Thr	missense_variant	Exon 33 of 47		NP_055889.2	O60333-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1 link	c.3787C>A	p.Pro1263Thr	missense_variant	Exon 35 of 49		NM_001365951.3	ENSP00000502065.1		O60333-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451076

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722668

show subpopulations

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:

9.07e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.77

.;D;.;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

0.0084

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

.;L;L;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.4

N;D;D;.;.

REVEL

Benign

0.27

Sift

Benign

0.21

T;T;T;.;.

Sift4G

Benign

0.51

T;T;T;T;T

Polyphen

0.020

B;B;.;B;.

Vest4

0.44

MutPred

0.30

.;Gain of catalytic residue at P1263 (P = 0.0381);Gain of catalytic residue at P1263 (P = 0.0381);.;.;

MVP

0.89

MPC

0.53

ClinPred

0.81

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.63

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over