rs2297881

chr1-10337509-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001365951.3(KIF1B):c.3398A>G(p.Tyr1133Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,614,184 control chromosomes in the GnomAD database, including 752 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. Y1133Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (113 hom., cov: 32)
  • Exomes 𝑓: 0.026 (639 hom.)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 9.32

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=0.007097006).
• BP6: Variant 1-10337509-A-G is Benign according to our data. Variant chr1-10337509-A-G is described in ClinVar as [Benign]. Clinvar id is 291567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10337509-A-G is described in Lovd as [Benign]. Variant chr1-10337509-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3	c.3398A>G	p.Tyr1133Cys	missense_variant	31/49	ENST00000676179.1
KIF1B	NM_001365952.1	c.3398A>G	p.Tyr1133Cys	missense_variant	31/49
KIF1B	NM_015074.3	c.3260A>G	p.Tyr1087Cys	missense_variant	29/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1	c.3398A>G	p.Tyr1133Cys	missense_variant	31/49		NM_001365951.3	P1

Frequencies

GnomAD3 genomes AF: 0.0345 AC: 5258 AN: 152194 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.0738

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0504

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0382

GnomAD3 exomes AF: 0.0327 AC: 8229 AN: 251464 Hom.: 151 AF XY: 0.0318 AC XY: 4319 AN XY: 135900

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.0290

Gnomad ASJ exome AF: 0.0464

Gnomad EAS exome AF: 0.0754

Gnomad SAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0465

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0367

GnomAD4 exome AF: 0.0255 AC: 37288 AN: 1461872 Hom.: 639 Cov.: 33 AF XY: 0.0254 AC XY: 18484 AN XY: 727240

Gnomad4 AFR exome AF: 0.0479

Gnomad4 AMR exome AF: 0.0301

Gnomad4 ASJ exome AF: 0.0465

Gnomad4 EAS exome AF: 0.0836

Gnomad4 SAS exome AF: 0.0258

Gnomad4 FIN exome AF: 0.0464

Gnomad4 NFE exome AF: 0.0204

Gnomad4 OTH exome AF: 0.0331

GnomAD4 genome AF: 0.0346 AC: 5266 AN: 152312 Hom.: 113 Cov.: 32 AF XY: 0.0354 AC XY: 2638 AN XY: 74462

Gnomad4 AFR AF: 0.0460

Gnomad4 AMR AF: 0.0312

Gnomad4 ASJ AF: 0.0521

Gnomad4 EAS AF: 0.0743

Gnomad4 SAS AF: 0.0265

Gnomad4 FIN AF: 0.0504

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.0392

Alfa AF: 0.0279 Hom.: 171

Bravo AF: 0.0347

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.0456 AC: 201

ESP6500EA AF: 0.0253 AC: 218

ExAC AF: 0.0325 AC: 3947

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0228

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

Charcot-Marie-Tooth disease type 2A1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 25, 2021

- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
MetaRNN	Benign	0.0071	T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.8	D;D;D;.;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.60
MPC		1.4
ClinPred		0.047	T
GERP RS		5.8
Varity_R		0.87
gMVP		0.76

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: rs2297881; hg19: chr1-10397567; COSMIC: COSV55805285;