rs139613776

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001365951.3(KIF1B):​c.608+8dup variant causes a splice region, 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. 1/1 splice prediction tools predicting alterations to normal splicing. 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 splice_region, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 1-10267565-T-TA is Benign according to our data. Variant chr1-10267565-T-TA is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 2854 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIF1BNM_001365951.3 linkuse as main transcriptc.608+8dup splice_region_variant, intron_variant ENST00000676179.1 NP_001352880.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KIF1BENST00000676179.1 linkuse as main transcriptc.608+8dup splice_region_variant, intron_variant NM_001365951.3 ENSP00000502065 P1O60333-1

Frequencies

GnomAD3 genomes
AF:
0.0188
AC:
2854
AN:
152154
Hom.:
41
Cov.:
32
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
GnomAD3 exomes
AF:
0.0184
AC:
4615
AN:
251268
Hom.:
78
AF XY:
0.0181
AC XY:
2460
AN XY:
135806
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 SAS exome
AF:
0.00284
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.:
32
AF XY:
0.0235
AC XY:
17069
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.00302
Gnomad4 AMR exome
AF:
0.00937
Gnomad4 ASJ exome
AF:
0.00658
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00223
Gnomad4 FIN exome
AF:
0.0404
Gnomad4 NFE exome
AF:
0.0277
Gnomad4 OTH exome
AF:
0.0200
GnomAD4 genome
AF:
0.0187
AC:
2854
AN:
152272
Hom.:
41
Cov.:
32
AF XY:
0.0191
AC XY:
1425
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.00464
Gnomad4 AMR
AF:
0.0141
Gnomad4 ASJ
AF:
0.00951
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.0442
Gnomad4 NFE
AF:
0.0279
Gnomad4 OTH
AF:
0.0114
Alfa
AF:
0.0216
Hom.:
9
Bravo
AF:
0.0156
Asia WGS
AF:
0.00289
AC:
10
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
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 22, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Charcot-Marie-Tooth disease Benign:1
Benign, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -
Neuroblastoma Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Charcot-Marie-Tooth disease type 2 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
KIF1B-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 09, 2024This 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

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

LitVar

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

Other links and lift over

dbSNP: rs139613776; hg19: chr1-10327623; API