1-10337509-A-G

Variant names:

• chr1-10337509-A-G
• rs2297881
• NM_001365951.3:c.3398A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 9.32
• Publications: 18 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365951.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	NM_001365951.3	MANE Select	c.3398A>G	p.Tyr1133Cys	missense	Exon 31 of 49	NP_001352880.1
	KIF1B	NM_001365952.1		c.3398A>G	p.Tyr1133Cys	missense	Exon 31 of 49	NP_001352881.1
	KIF1B	NM_015074.3		c.3260A>G	p.Tyr1087Cys	missense	Exon 29 of 47	NP_055889.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	ENST00000676179.1	MANE Select	c.3398A>G	p.Tyr1133Cys	missense	Exon 31 of 49	ENSP00000502065.1
	KIF1B	ENST00000377081.5	TSL:1	c.3398A>G	p.Tyr1133Cys	missense	Exon 30 of 48	ENSP00000366284.1
	KIF1B	ENST00000377086.5	TSL:1	c.3398A>G	p.Tyr1133Cys	missense	Exon 31 of 49	ENSP00000366290.1

Frequencies

GnomAD3 genomes AF: 0.0345 AC: 5258 AN: 152194 Hom.: 111 Cov.: 32

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

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.: 33 AF XY: 0.0254 AC XY: 18484 AN XY: 727240

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

GnomAD4 genome AF: 0.0346 AC: 5266 AN: 152312 Hom.: 113 Cov.: 32 AF XY: 0.0354 AC XY: 2638 AN XY: 74462

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: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0219 AC: 1487 AN: 68012

Other (OTH) AF: 0.0392 AC: 83 AN: 2116

Alfa AF: 0.0282 Hom.: 361

Bravo AF: 0.0347

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0252 AC: 97

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:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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.

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

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Hereditary cancer-predisposing syndrome Benign:1

Jul 22, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1 c.3260A>G, located in exon 29 of the KIF1B gene, is predicted to result in the substitution of tyrosine with cysteine at codon 1087, p.(Tyr1087Cys). The variant allele was found in 8932/268326 alleles (173 homozygous), with a filtering allele frequency of 3.25% at 99% confidence, in the gnomAD v2.1.1 database (non-cancer data set) (BA1). The SpliceAI algorithm predicts no significant impact on splicing, and the REVEL meta-predictor score for this variant (0.623) is indeterminate regarding the effect that it may have on protein function according to Pejaver 2022 thresholds (PMID: 36413997). In vitro studies in mouse cells showed that the mutation reduces Kif1b's ability to bind and transport Igf1r to the axon, and failed to rescue axonal growth defects in Kif1b-null neurons; however, neither pathogenic nor neutral controls were not included in the analysis (PMID 30126838). This variant has been identified in the ClinVar database (9x benign, 1x pathogenic) but has not been identified in the LOVD database. Based on currently available information, c.3260A>G is classified as a benign variant according ACMG guidelines.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0071	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MPC		1.4
ClinPred		0.047	T
GERP RS		5.8
Varity_R		0.87
gMVP		0.76
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2297881; hg19: chr1-10397567; COSMIC: COSV55805285;