NM_001365951.3:c.608+8dupA

Variant names:

• chr1-10267565-T-TA
• rs139613776
• NM_001365951.3:c.608+8dupA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.15

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]

ACMG classification

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 rank	MANE	Protein	UniProt
KIF1B	NM_001365951.3	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	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.: 41 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Benign:3

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

- -

-

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. -

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

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

Other links and lift over

dbSNP: rs139613776; hg19: chr1-10327623;