rs2297881

Positions:

chr1-10337509-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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:8

Conservation

PhyloP100: 9.32

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 -19 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 5.2436 (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=0.007097006).

BP6

Variant 1-10337509-A-G is Benign according to our data. Variant chr1-10337509-A-G is described in ClinVar as [Benign]. Clinvar id is 291567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10337509-A-G is described in Lovd as [Benign]. Variant chr1-10337509-A-G is described in Lovd as [Likely_benign].

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/exons	MANE
KIF1B	NM_001365951.3 linkuse as main transcript	c.3398A>G	p.Tyr1133Cys	missense_variant	31/49	ENST00000676179.1
KIF1B	NM_001365952.1 linkuse as main transcript	c.3398A>G	p.Tyr1133Cys	missense_variant	31/49
KIF1B	NM_015074.3 linkuse as main transcript	c.3260A>G	p.Tyr1087Cys	missense_variant	29/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1 linkuse as main transcript	c.3398A>G	p.Tyr1133Cys	missense_variant	31/49		NM_001365951.3	P1	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

GnomAD3 exomes

AF:

0.0327

AC:

8229

AN:

251464

Hom.:

151

AF XY:

0.0318

AC XY:

4319

AN XY:

135900

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 SAS exome

AF:

0.0241

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

Gnomad4 AFR exome

AF:

0.0479

Gnomad4 AMR exome

AF:

0.0301

Gnomad4 ASJ exome

AF:

0.0465

Gnomad4 EAS exome

AF:

0.0836

Gnomad4 SAS exome

AF:

0.0258

Gnomad4 FIN exome

AF:

0.0464

Gnomad4 NFE exome

AF:

0.0204

Gnomad4 OTH exome

AF:

0.0331

GnomAD4 genome

AF:

0.0346

AC:

5266

AN:

152312

Hom.:

113

Cov.:

AF XY:

0.0354

AC XY:

2638

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0460

Gnomad4 AMR

AF:

0.0312

Gnomad4 ASJ

AF:

0.0521

Gnomad4 EAS

AF:

0.0743

Gnomad4 SAS

AF:

0.0265

Gnomad4 FIN

AF:

0.0504

Gnomad4 NFE

AF:

0.0219

Gnomad4 OTH

AF:

0.0392

Alfa

AF:

0.0279

Hom.:

171

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 2020	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease type 2A1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 25, 2021

- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Neuroblastoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

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;.;.

MutationTaster

Benign

1.0

D;D;D

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

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