rs2297881

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001365951.3(KIF1B):c.3398A>G(p.Tyr1133Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,614,184 control chromosomes in the GnomAD database, including 752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y1133Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 113 hom., cov: 32)

Exomes 𝑓: 0.026 ( 639 hom. )

Consequence

KIF1B
NM_001365951.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 9.32

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

pheochromocytoma
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 2A1
Inheritance: AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neuroblastoma, susceptibility to, 1
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KIF1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007097006).

BP6

Variant 1-10337509-A-G is Benign according to our data. Variant chr1-10337509-A-G is described in ClinVar as Benign. ClinVar VariationId is 291567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1B	NM_001365951.3 link	c.3398A>G	p.Tyr1133Cys	missense_variant	Exon 31 of 49	ENST00000676179.1	NP_001352880.1
KIF1B	NM_001365952.1 link	c.3398A>G	p.Tyr1133Cys	missense_variant	Exon 31 of 49		NP_001352881.1
KIF1B	NM_015074.3 link	c.3260A>G	p.Tyr1087Cys	missense_variant	Exon 29 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.3398A>G	p.Tyr1133Cys	missense_variant	Exon 31 of 49		NM_001365951.3	ENSP00000502065.1		O60333-1

Frequencies

GnomAD3 genomes

AF:

0.0345

AC:

5258

AN:

152194

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0460

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0312

Gnomad ASJ

AF:

0.0521

Gnomad EAS

AF:

0.0738

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.0504

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0219

Gnomad OTH

AF:

0.0382

GnomAD2 exomes

AF:

0.0327

AC:

8229

AN:

251464

AF XY:

0.0318

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.0290

Gnomad ASJ exome

AF:

0.0464

Gnomad EAS exome

AF:

0.0754

Gnomad FIN exome

AF:

0.0465

Gnomad NFE exome

AF:

0.0232

Gnomad OTH exome

AF:

0.0367

GnomAD4 exome

AF:

0.0255

AC:

37288

AN:

1461872

Hom.:

639

Cov.:

AF XY:

0.0254

AC XY:

18484

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0479

AC:

1603

AN:

33480

American (AMR)

AF:

0.0301

AC:

1345

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0465

AC:

1216

AN:

26134

East Asian (EAS)

AF:

0.0836

AC:

3318

AN:

39700

South Asian (SAS)

AF:

0.0258

AC:

2225

AN:

86258

European-Finnish (FIN)

AF:

0.0464

AC:

2479

AN:

53418

Middle Eastern (MID)

AF:

0.0817

AC:

471

AN:

5768

European-Non Finnish (NFE)

AF:

0.0204

AC:

22630

AN:

1111996

Other (OTH)

AF:

0.0331

AC:

2001

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2111

4223

6334

8446

10557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

912

1824

2736

3648

4560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0346

AC:

5266

AN:

152312

Hom.:

113

Cov.:

AF XY:

0.0354

AC XY:

2638

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0460

AC:

1914

AN:

41574

American (AMR)

AF:

0.0312

AC:

477

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0521

AC:

181

AN:

3472

East Asian (EAS)

AF:

0.0743

AC:

385

AN:

5180

South Asian (SAS)

AF:

0.0265

AC:

128

AN:

4828

European-Finnish (FIN)

AF:

0.0504

AC:

535

AN:

10616

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0219

AC:

1487

AN:

68012

Other (OTH)

AF:

0.0392

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

257

515

772

1030

1287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0282

Hom.:

361

Bravo

AF:

0.0347

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.0456

AC:

201

ESP6500EA

AF:

0.0253

AC:

218

ExAC

AF:

0.0325

AC:

3947

Asia WGS

AF:

0.0600

AC:

209

AN:

3478

EpiCase

AF:

0.0266

EpiControl

AF:

0.0228

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease type 2A1

Pathogenic:1

Mar 25, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2A1;C2749485:Neuroblastoma, susceptibility to, 1

Benign:1

Feb 05, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Neuroblastoma

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;D;.;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D

MetaRNN

Benign

0.0071

T;T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.5

.;M;M;.;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.8

D;D;D;.;.

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;D;D;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;.;D;.

Vest4

0.60

MPC

1.4

ClinPred

0.047

GERP RS

5.8

Varity_R

0.87

gMVP

0.76

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over