rs551543997

Variant names:

• chr1-10321744-T-C
• rs551543997
• NM_001365951.3:c.2245T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365951.3(KIF1B):​c.2245T>C​(p.Trp749Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,204 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts 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. W749C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00072 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.66
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009395182).
• BP6: Variant 1-10321744-T-C is Benign according to our data. Variant chr1-10321744-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000715 (109/152352) while in subpopulation SAS AF = 0.0215 (104/4826). AF 95% confidence interval is 0.0182. There are 5 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 109 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	NM_001365951.3	MANE Select	c.2245T>C	p.Trp749Arg	missense	Exon 24 of 49	NP_001352880.1	O60333-1
	KIF1B	NM_001365952.1		c.2245T>C	p.Trp749Arg	missense	Exon 24 of 49	NP_001352881.1	O60333-1
	KIF1B	NM_015074.3		c.2107T>C	p.Trp703Arg	missense	Exon 22 of 47	NP_055889.2	O60333-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	ENST00000676179.1	MANE Select	c.2245T>C	p.Trp749Arg	missense	Exon 24 of 49	ENSP00000502065.1	O60333-1
	KIF1B	ENST00000377081.5	TSL:1	c.2245T>C	p.Trp749Arg	missense	Exon 23 of 48	ENSP00000366284.1	O60333-4
	KIF1B	ENST00000377086.5	TSL:1	c.2245T>C	p.Trp749Arg	missense	Exon 24 of 49	ENSP00000366290.1	O60333-1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152234 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00286 AC: 720 AN: 251420 AF XY: 0.00392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00141 AC: 2060 AN: 1461852 Hom.: 35 Cov.: 31 AF XY: 0.00201 AC XY: 1465 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0219 AC: 1888 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111976

Other (OTH) AF: 0.00152 AC: 92 AN: 60396

GnomAD4 genome AF: 0.000715 AC: 109 AN: 152352 Hom.: 5 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74502

African (AFR) AF: 0.0000721 AC: 3 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0215 AC: 104 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000310 Hom.: 1

Bravo AF: 0.000159

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00329 AC: 399

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Neuroblastoma (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.38	T
Polyphen		0.99	D
Vest4		0.84
MutPred		0.43		Gain of disorder (P = 0.0151)
MVP		0.65
MPC		1.7
ClinPred		0.11	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.78
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs551543997; hg19: chr1-10381802; COSMIC: COSV55811150;