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]

KIF1B links:

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 GnomAd at 2854 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3 linkuse as main transcript	c.608+8dup		splice_region_variant, intron_variant		ENST00000676179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1 linkuse as main transcript	c.608+8dup		splice_region_variant, intron_variant			NM_001365951.3	P1	O60333-1

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

GnomAD3 exomes

AF:

0.0184

AC:

4615

AN:

251268

Hom.:

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.:

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.:

Cov.:

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.:

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Department 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. -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Neuroblastoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Charcot-Marie-Tooth disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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.

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