rs138324955

Variant names:

• chr1-10258485-CTT-C
• rs138324955
• NM_001365951.3:c.184-6_184-5delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001365951.3(KIF1B):​c.184-6_184-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,613,084 control chromosomes in the GnomAD database, including 565 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (40 hom., cov: 32)
  • Exomes 𝑓: 0.024 (525 hom.)
• Consequence: KIF1B NM_001365951.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.16
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 1-10258485-CTT-C is Benign according to our data. Variant chr1-10258485-CTT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260541.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 (2851/152234) while in subpopulation NFE AF = 0.0279 (1897/67990). AF 95% confidence interval is 0.0269. There are 40 homozygotes in GnomAd4. There are 1418 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2851 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.184-6_184-5delTT		splice_region_variant, intron_variant	Intron 3 of 48	ENST00000676179.1	NP_001352880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.184-7_184-6delTT		splice_region_variant, intron_variant	Intron 3 of 48		NM_001365951.3	ENSP00000502065.1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2851 AN: 152116 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0183 AC: 4593 AN: 251318 AF XY: 0.0180

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.00969

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0425

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0237 AC: 34668 AN: 1460850 Hom.: 525 AF XY: 0.0232 AC XY: 16887 AN XY: 726828

African (AFR) AF: 0.00299 AC: 100 AN: 33470

American (AMR) AF: 0.00937 AC: 419 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00658 AC: 172 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.00220 AC: 190 AN: 86222

European-Finnish (FIN) AF: 0.0404 AC: 2157 AN: 53406

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0274 AC: 30414 AN: 1111088

Other (OTH) AF: 0.0198 AC: 1198 AN: 60364

GnomAD4 genome AF: 0.0187 AC: 2851 AN: 152234 Hom.: 40 Cov.: 32 AF XY: 0.0191 AC XY: 1418 AN XY: 74432

African (AFR) AF: 0.00460 AC: 191 AN: 41548

American (AMR) AF: 0.0141 AC: 216 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.0443 AC: 469 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0279 AC: 1897 AN: 67990

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.0200 Hom.: 7

Bravo AF: 0.0156

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0222

EpiControl AF: 0.0244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 24, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138324955; hg19: chr1-10318543;