chr1-10324838-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001365951.3(KIF1B):c.2618C>T(p.Thr873Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,614,138 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T873S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 3 hom. )

Consequence

KIF1B
NM_001365951.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5O:1

Conservation

PhyloP100: 2.73

Publications

10 publications found

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 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: ClinGen, Orphanet, Ambry Genetics, 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

KIF1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017159462).

BP6

Variant 1-10324838-C-T is Benign according to our data. Variant chr1-10324838-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4660.

BS2

High AC in GnomAd4 at 66 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365951.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF1B	NM_001365951.3	MANE Select	c.2618C>T	p.Thr873Ile	missense	Exon 26 of 49	NP_001352880.1	O60333-1
KIF1B	NM_001365952.1		c.2618C>T	p.Thr873Ile	missense	Exon 26 of 49	NP_001352881.1	O60333-1
KIF1B	NM_015074.3		c.2480C>T	p.Thr827Ile	missense	Exon 24 of 47	NP_055889.2	O60333-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF1B	ENST00000676179.1	MANE Select	c.2618C>T	p.Thr873Ile	missense	Exon 26 of 49	ENSP00000502065.1	O60333-1
KIF1B	ENST00000377081.5	TSL:1	c.2618C>T	p.Thr873Ile	missense	Exon 25 of 48	ENSP00000366284.1	O60333-4
KIF1B	ENST00000377086.5	TSL:1	c.2618C>T	p.Thr873Ile	missense	Exon 26 of 49	ENSP00000366290.1	O60333-1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000608

AC:

153

AN:

251484

AF XY:

0.000640

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000624

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000482

AC:

705

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000554

AC XY:

403

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00151

AC:

130

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000386

AC:

429

AN:

1112004

Other (OTH)

AF:

0.000861

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000433

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41548

American (AMR)

AF:

0.000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000724

Hom.:

Bravo

AF:

0.000570

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000626

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 2 (1)

Charcot-Marie-Tooth disease type 2A1;C2749485:Neuroblastoma, susceptibility to, 1 (1)

KIF1B-related disorder (1)

Malignant tumor of breast (1)

Neuroblastoma (1)

not specified (1)

Neuroblastoma, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.025

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

PhyloP100

2.7

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.43

REVEL

Uncertain

0.33

Sift

Benign

0.30

Sift4G

Benign

0.47

Polyphen

0.0090

Vest4

0.54

MVP

0.88

MPC

0.46

ClinPred

0.091

GERP RS

4.9

Varity_R

0.053

gMVP

0.33

Mutation Taster

=3/97

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over