1-10376568-C-T

Position:

chr1-10376568-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365951.3(KIF1B):c.5432C>T(p.Pro1811Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00216 in 1,613,824 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1811T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 37 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 31 hom. )

Consequence

KIF1B
NM_001365951.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.74

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.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1B. . Gene score misZ 3.599 (greater than the threshold 3.09). Trascript score misZ 5.2436 (greater than threshold 3.09). GenCC has associacion of gene with pheochromocytoma, neuroblastoma, susceptibility to, 1, hereditary pheochromocytoma-paraganglioma, Charcot-Marie-Tooth disease type 2A1.

BP4

Computational evidence support a benign effect (MetaRNN=0.001927644).

BP6

Variant 1-10376568-C-T is Benign according to our data. Variant chr1-10376568-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10376568-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1801/152240) while in subpopulation AFR AF= 0.0403 (1675/41560). AF 95% confidence interval is 0.0387. There are 37 homozygotes in gnomad4. There are 860 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1801 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3 linkuse as main transcript	c.5432C>T	p.Pro1811Leu	missense_variant	49/49	ENST00000676179.1	NP_001352880.1
KIF1B	NM_001365952.1 linkuse as main transcript	c.5432C>T	p.Pro1811Leu	missense_variant	49/49		NP_001352881.1
KIF1B	NM_015074.3 linkuse as main transcript	c.5294C>T	p.Pro1765Leu	missense_variant	47/47		NP_055889.2	O60333-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1 linkuse as main transcript	c.5432C>T	p.Pro1811Leu	missense_variant	49/49		NM_001365951.3	ENSP00000502065.1		O60333-1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1799

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0404

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00701

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00302

AC:

757

AN:

250502

Hom.:

AF XY:

0.00204

AC XY:

276

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0425

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000972

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00115

AC:

1681

AN:

1461584

Hom.:

Cov.:

AF XY:

0.000976

AC XY:

710

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0419

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.00212

GnomAD4 genome

AF:

0.0118

AC:

1801

AN:

152240

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

860

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0403

Gnomad4 AMR

AF:

0.00700

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.0136

ESP6500AA

AF:

0.0424

AC:

187

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00372

AC:

452

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

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

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Likely 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

- -

not specified

Benign:1

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. -

Neuroblastoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

-0.090

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.14

.;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.063

T;T

Polyphen

0.021

B;B

Vest4

0.10

MVP

0.22

MPC

0.43

ClinPred

0.017

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.075

gMVP

0.37

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