rs138324955

chr1-10258485-CTT-C

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.184-6_184-5del variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.16

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 1-10258485-CTT-C is Benign according to our data. Variant chr1-10258485-CTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 260541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10258485-CTT-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2851 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3	c.184-6_184-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000676179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1	c.184-6_184-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001365951.3	P1

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

GnomAD3 exomes AF: 0.0183 AC: 4593 AN: 251318 Hom.: 79 AF XY: 0.0180 AC XY: 2449 AN XY: 135830

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 SAS exome AF: 0.00284

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

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00937

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0274

Gnomad4 OTH exome AF: 0.0198

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

Gnomad4 AFR AF: 0.00460

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0443

Gnomad4 NFE AF: 0.0279

Gnomad4 OTH AF: 0.0114

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

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2020	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. -

not provided Benign:2

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	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs138324955; hg19: chr1-10318543;