chr1-10376568-C-T

Variant names:

• chr1-10376568-C-T
• rs61999305
• NM_001365951.3:c.5432C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365951.3(KIF1B):​c.5432C>T​(p.Pro1811Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00216 in 1,613,824 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P1811T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (31 hom.)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.74
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001927644).
• BP6: Variant 1-10376568-C-T is Benign according to our data. Variant chr1-10376568-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1801/152240) while in subpopulation AFR AF = 0.0403 (1675/41560). AF 95% confidence interval is 0.0387. There are 37 homozygotes in GnomAd4. There are 860 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1801 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.5432C>T	p.Pro1811Leu	missense	Exon 49 of 49	NP_001352880.1	O60333-1
	KIF1B	NM_001365952.1		c.5432C>T	p.Pro1811Leu	missense	Exon 49 of 49	NP_001352881.1	O60333-1
	KIF1B	NM_015074.3		c.5294C>T	p.Pro1765Leu	missense	Exon 47 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.5432C>T	p.Pro1811Leu	missense	Exon 49 of 49	ENSP00000502065.1	O60333-1
	KIF1B	ENST00000377086.5	TSL:1	c.5432C>T	p.Pro1811Leu	missense	Exon 49 of 49	ENSP00000366290.1	O60333-1
	KIF1B	ENST00000263934.10	TSL:1	c.5294C>T	p.Pro1765Leu	missense	Exon 47 of 47	ENSP00000263934.6	O60333-2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1799 AN: 152122 Hom.: 37 Cov.: 31

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00302 AC: 757 AN: 250502 AF XY: 0.00204

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000972

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00115 AC: 1681 AN: 1461584 Hom.: 31 Cov.: 31 AF XY: 0.000976 AC XY: 710 AN XY: 727096

African (AFR) AF: 0.0419 AC: 1403 AN: 33474

American (AMR) AF: 0.00197 AC: 88 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5758

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111904

Other (OTH) AF: 0.00212 AC: 128 AN: 60366

GnomAD4 genome AF: 0.0118 AC: 1801 AN: 152240 Hom.: 37 Cov.: 31 AF XY: 0.0116 AC XY: 860 AN XY: 74432

African (AFR) AF: 0.0403 AC: 1675 AN: 41560

American (AMR) AF: 0.00700 AC: 107 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00261 Hom.: 9

Bravo AF: 0.0136

ESP6500AA AF: 0.0424 AC: 187

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00372 AC: 452

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	Benign	0.095
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.14	N
PhyloP100		3.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.063	T
Polyphen		0.021	B
Vest4		0.10
MVP		0.22
MPC		0.43
ClinPred		0.017	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.37
Mutation Taster		=92/8	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: rs61999305; hg19: chr1-10436626;