rs148481786

Positions:

chr1-10304202-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The ENST00000377083.5(KIF1B):c.3017A>G(p.Glu1006Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 1,614,182 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 40 hom. )

Consequence

KIF1B
ENST00000377083.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.47

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1B. . Gene score misZ 3.599 (greater than the threshold 3.09). Trascript score misZ 3.3773 (greater than threshold 3.09). GenCC has associacion of gene with pheochromocytoma, neuroblastoma, susceptibility to, 1, hereditary pheochromocytoma-paraganglioma, Charcot-Marie-Tooth disease type 2A1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034499764).

BP6

Variant 1-10304202-A-G is Benign according to our data. Variant chr1-10304202-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 283154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10304202-A-G is described in Lovd as [Benign]. Variant chr1-10304202-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 770 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3 linkuse as main transcript	c.2115+6956A>G		intron_variant		ENST00000676179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1 linkuse as main transcript	c.2115+6956A>G		intron_variant			NM_001365951.3	P1	O60333-1

Frequencies

GnomAD3 genomes

AF:

0.00506

AC:

770

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00650

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00583

AC:

1463

AN:

250956

Hom.:

AF XY:

0.00565

AC XY:

767

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.000622

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.0285

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.00646

Gnomad OTH exome

AF:

0.00917

GnomAD4 exome

AF:

0.00558

AC:

8151

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

4020

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00266

Gnomad4 ASJ exome

AF:

0.0271

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00242

Gnomad4 FIN exome

AF:

0.0109

Gnomad4 NFE exome

AF:

0.00555

Gnomad4 OTH exome

AF:

0.00551

GnomAD4 genome

AF:

0.00506

AC:

770

AN:

152312

Hom.:

Cov.:

AF XY:

0.00509

AC XY:

379

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.0282

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0108

Gnomad4 NFE

AF:

0.00650

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00668

Hom.:

Bravo

AF:

0.00454

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00611

AC:

742

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KIF1B: PP2, BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KIF1B p.Glu1006Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs148481786) and ClinVar (classified as benign by EGL Genetics and likely benign by Children's Mercy Hospital) The variant was identified in control databases in 1644 of 282350 chromosomes (14 homozygous) at a frequency of 0.005823 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 290 of 10356 chromosomes (freq: 0.028), European (Finnish) in 249 of 25120 chromosomes (freq: 0.009912), Other in 67 of 7192 chromosomes (freq: 0.009316), European (non-Finnish) in 859 of 128920 chromosomes (freq: 0.006663), Latino in 89 of 35424 chromosomes (freq: 0.002512), South Asian in 71 of 30614 chromosomes (freq: 0.002319) and African in 19 of 24776 chromosomes (freq: 0.000767), while the variant was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu1006 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 04, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

KIF1B-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.037

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.40

.;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.71

MutationTaster

Benign

1.0

D;D;D;N;N

PROVEAN

Benign

0.060

N;N

REVEL

Benign

0.095

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.36

T;T

Polyphen

0.45

B;B

Vest4

0.15

MVP

0.41

ClinPred

0.018

GERP RS

4.4

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over