rs117525287

chr1-10321829-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365951.3(KIF1B):c.2330A>G(p.Asn777Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00202 in 1,614,194 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (45 hom.)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.04

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KIF1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.008233219).
• BP6: Variant 1-10321829-A-G is Benign according to our data. Variant chr1-10321829-A-G is described in ClinVar as [Benign]. Clinvar id is 240957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10321829-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0027 (412/152334) while in subpopulation EAS AF= 0.0425 (220/5182). AF 95% confidence interval is 0.0379. There are 10 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3	c.2330A>G	p.Asn777Ser	missense_variant	24/49	ENST00000676179.1
KIF1B	NM_001365952.1	c.2330A>G	p.Asn777Ser	missense_variant	24/49
KIF1B	NM_015074.3	c.2192A>G	p.Asn731Ser	missense_variant	22/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1	c.2330A>G	p.Asn777Ser	missense_variant	24/49		NM_001365951.3	P1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152216 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0422

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00483 AC: 1214 AN: 251392 Hom.: 14 AF XY: 0.00434 AC XY: 590 AN XY: 135868

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0435

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00194 AC: 2841 AN: 1461860 Hom.: 45 Cov.: 31 AF XY: 0.00186 AC XY: 1351 AN XY: 727238

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152334 Hom.: 10 Cov.: 32 AF XY: 0.00338 AC XY: 252 AN XY: 74494

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0425

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00200 Hom.: 8

Bravo AF: 0.00204

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00467 AC: 567

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.055
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0082	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.1	D;D;D;.;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.010	D;D;D;.;.
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		0.97	D;D;.;D;.
Vest4		0.38
MVP		0.86
MPC		1.1
ClinPred		0.049	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.85

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

Other links and lift over

dbSNP: rs117525287; hg19: chr1-10381887; COSMIC: COSV99822602;