rs139613776

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_001365951.3(KIF1B):c.608+8dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,613,808 control chromosomes in the GnomAD database, including 576 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 41 hom., cov: 32)

Exomes 𝑓: 0.024 ( 535 hom. )

Consequence

KIF1B
NM_001365951.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.15

Publications

1 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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 1-10267565-T-TA is Benign according to our data. Variant chr1-10267565-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0187 (2854/152272) while in subpopulation NFE AF = 0.0279 (1898/68024). AF 95% confidence interval is 0.0269. There are 41 homozygotes in GnomAd4. There are 1425 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2854 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1B	NM_001365951.3 link	c.608+8dupA		intron_variant	Intron 6 of 48	ENST00000676179.1	NP_001352880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1 link	c.608+7_608+8insA		splice_region_variant, intron_variant	Intron 6 of 48		NM_001365951.3	ENSP00000502065.1

Frequencies

GnomAD3 genomes

AF:

0.0188

AC:

2854

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0442

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0279

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0184

AC:

4615

AN:

251268

AF XY:

0.0181

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.00971

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0426

Gnomad NFE exome

AF:

0.0265

Gnomad OTH exome

AF:

0.0214

GnomAD4 exome

AF:

0.0240

AC:

35066

AN:

1461536

Hom.:

535

Cov.:

AF XY:

0.0235

AC XY:

17069

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.00302

AC:

101

AN:

33472

American (AMR)

AF:

0.00937

AC:

419

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00658

AC:

172

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.00223

AC:

192

AN:

86248

European-Finnish (FIN)

AF:

0.0404

AC:

2158

AN:

53402

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0277

AC:

30801

AN:

1111746

Other (OTH)

AF:

0.0200

AC:

1205

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1658

3316

4975

6633

8291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1120

2240

3360

4480

5600

<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:

0.0187

AC:

2854

AN:

152272

Hom.:

Cov.:

AF XY:

0.0191

AC XY:

1425

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00464

AC:

193

AN:

41556

American (AMR)

AF:

0.0141

AC:

216

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0442

AC:

469

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0279

AC:

1898

AN:

68024

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

148

296

443

591

739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0216

Hom.:

Bravo

AF:

0.0156

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0223

EpiControl

AF:

0.0245

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The KIF1B c.608+8dupA variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs139613776), ClinVar (classified as benign by Invitae and Prevention Genetics in 2017, likely benign by Illumina in 2016) and LOVD 3.0. The variant was identified in control databases in 5227 of 282654 chromosomes (87 homozygous) at a frequency of 0.018493 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: European (Finnish) in 1053 of 25122 chromosomes (freq: 0.04192), European (non-Finnish) in 3413 of 129024 chromosomes (freq: 0.02645), Other in 155 of 7216 chromosomes (freq: 0.02148), Latino in 346 of 35434 chromosomes (freq: 0.009765), Ashkenazi Jewish in 70 of 10360 chromosomes (freq: 0.006757), African in 102 of 24956 chromosomes (freq: 0.004087), South Asian in 87 of 30614 chromosomes (freq: 0.002842), and East Asian in 1 of 19928 chromosomes (freq: 0.00005). The variant occurs outside of the splicing consensus sequence however 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict the creation of a new 5' splice site; this is not very predictive of 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.

Oct 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Neuroblastoma

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

KIF1B-related disorder

Benign:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.67

Position offset: -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