chr1-10258594-C-G

Position:

chr1-10258594-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001365951.3(KIF1B):c.285C>G(p.Ala95Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,504 control chromosomes in the GnomAD database, including 67,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A95A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.24 ( 4968 hom., cov: 32)

Exomes 𝑓: 0.29 ( 62311 hom. )

Consequence

KIF1B
NM_001365951.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.0670

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 1-10258594-C-G is Benign according to our data. Variant chr1-10258594-C-G is described in ClinVar as [Benign]. Clinvar id is 129399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10258594-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.067 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3 linkuse as main transcript	c.285C>G	p.Ala95Ala	synonymous_variant	4/49	ENST00000676179.1	NP_001352880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1 linkuse as main transcript	c.285C>G	p.Ala95Ala	synonymous_variant	4/49		NM_001365951.3	ENSP00000502065.1		O60333-1

Frequencies

GnomAD3 genomes

AF:

0.237

AC:

36045

AN:

151954

Hom.:

4955

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0922

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.310

Gnomad ASJ

AF:

0.266

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.291

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.294

Gnomad OTH

AF:

0.254

GnomAD3 exomes

AF:

0.277

AC:

69540

AN:

251442

Hom.:

10171

AF XY:

0.275

AC XY:

37353

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.0864

Gnomad AMR exome

AF:

0.345

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.292

Gnomad SAS exome

AF:

0.229

Gnomad FIN exome

AF:

0.293

Gnomad NFE exome

AF:

0.291

Gnomad OTH exome

AF:

0.265

GnomAD4 exome

AF:

0.289

AC:

422278

AN:

1461432

Hom.:

62311

Cov.:

AF XY:

0.288

AC XY:

209040

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0806

Gnomad4 AMR exome

AF:

0.337

Gnomad4 ASJ exome

AF:

0.271

Gnomad4 EAS exome

AF:

0.256

Gnomad4 SAS exome

AF:

0.226

Gnomad4 FIN exome

AF:

0.301

Gnomad4 NFE exome

AF:

0.300

Gnomad4 OTH exome

AF:

0.281

GnomAD4 genome

AF:

0.237

AC:

36076

AN:

152072

Hom.:

4968

Cov.:

AF XY:

0.238

AC XY:

17697

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0921

Gnomad4 AMR

AF:

0.311

Gnomad4 ASJ

AF:

0.266

Gnomad4 EAS

AF:

0.283

Gnomad4 SAS

AF:

0.239

Gnomad4 FIN

AF:

0.291

Gnomad4 NFE

AF:

0.294

Gnomad4 OTH

AF:

0.259

Alfa

AF:

0.240

Hom.:

1541

Bravo

AF:

0.235

EpiCase

AF:

0.294

EpiControl

AF:

0.295

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2013	The Ala95Ala variant in KIF1B: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, has been identified in 30% (2553/8600) of Europe an American chromosomes and 9% (403/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1240 2052). -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Pheochromocytoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Neuroblastoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Charcot-Marie-Tooth disease type 2A1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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