rs77172218

Positions:

• chr1-10368512-G-A
• chr1-10368512-G-C

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.4798G>A​(p.Val1600Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,613,930 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 32)
  • Exomes 𝑓: 0.015 (164 hom.)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.40

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=0.0055160522).
• BP6: Variant 1-10368512-G-A is Benign according to our data. Variant chr1-10368512-G-A is described in ClinVar as [Benign]. Clinvar id is 240959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10368512-G-A is described in Lovd as [Benign]. Variant chr1-10368512-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1631/152292) while in subpopulation NFE AF= 0.0179 (1218/68032). AF 95% confidence interval is 0.0171. There are 13 homozygotes in gnomad4. There are 757 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3	c.4798G>A	p.Val1600Met	missense_variant	44/49	ENST00000676179.1
KIF1B	NM_001365952.1	c.4798G>A	p.Val1600Met	missense_variant	44/49
KIF1B	NM_015074.3	c.4660G>A	p.Val1554Met	missense_variant	42/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1	c.4798G>A	p.Val1600Met	missense_variant	44/49		NM_001365951.3	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1630 AN: 152174 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00994 AC: 2500 AN: 251470 Hom.: 26 AF XY: 0.0102 AC XY: 1393 AN XY: 135910

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.0146 AC: 21285 AN: 1461638 Hom.: 164 Cov.: 31 AF XY: 0.0143 AC XY: 10421 AN XY: 727140

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.00451

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.0132

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0107 AC: 1631 AN: 152292 Hom.: 13 Cov.: 32 AF XY: 0.0102 AC XY: 757 AN XY: 74480

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0151 Hom.: 35

Bravo AF: 0.00967

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0169 AC: 145

ExAC AF: 0.0101 AC: 1231

EpiCase AF: 0.0146

EpiControl AF: 0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -
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	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0055
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
MetaRNN	Benign	0.0055	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.59	N;N;N;.;.
REVEL	Benign	0.061
Sift	Benign	0.076	T;T;T;.;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.0050	B;B;.;B;.
Vest4		0.28
MPC		0.43
ClinPred		0.0054	T
GERP RS		4.4
Varity_R		0.074
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77172218; hg19: chr1-10428570; COSMIC: COSV99028891; COSMIC: COSV99028891;