rs77172218

Variant names:

• chr1-10368512-G-A
• rs77172218
• NM_001365951.3:c.4798G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-10368512-G-A
• chr1-10368512-G-C
• chr1-10368512-G-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.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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1600G) has been classified as Uncertain significance.

• 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:10
• Conservation: PhyloP100: 3.40
• Publications: 12 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=0.0055160522).
• BP6: Variant 1-10368512-G-A is Benign according to our data. Variant chr1-10368512-G-A is described in ClinVar as Benign. ClinVar VariationId is 240959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1631 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.4798G>A	p.Val1600Met	missense	Exon 44 of 49	NP_001352880.1	O60333-1
	KIF1B	NM_001365952.1		c.4798G>A	p.Val1600Met	missense	Exon 44 of 49	NP_001352881.1	O60333-1
	KIF1B	NM_015074.3		c.4660G>A	p.Val1554Met	missense	Exon 42 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.4798G>A	p.Val1600Met	missense	Exon 44 of 49	ENSP00000502065.1	O60333-1
	KIF1B	ENST00000377081.5	TSL:1	c.4798G>A	p.Val1600Met	missense	Exon 43 of 48	ENSP00000366284.1	O60333-4
	KIF1B	ENST00000377086.5	TSL:1	c.4798G>A	p.Val1600Met	missense	Exon 44 of 49	ENSP00000366290.1	O60333-1

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

GnomAD2 exomes AF: 0.00994 AC: 2500 AN: 251470 AF XY: 0.0102

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 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

African (AFR) AF: 0.00212 AC: 71 AN: 33476

American (AMR) AF: 0.00371 AC: 166 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00451 AC: 118 AN: 26136

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

South Asian (SAS) AF: 0.00225 AC: 194 AN: 86246

European-Finnish (FIN) AF: 0.0132 AC: 707 AN: 53402

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0173 AC: 19276 AN: 1111806

Other (OTH) AF: 0.0123 AC: 745 AN: 60394

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

African (AFR) AF: 0.00277 AC: 115 AN: 41544

American (AMR) AF: 0.00673 AC: 103 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

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

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.0122 AC: 130 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0179 AC: 1218 AN: 68032

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0141 Hom.: 42

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Neuroblastoma (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0055
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.061
Sift	Benign	0.076	T
Sift4G	Benign	0.14	T
Polyphen		0.0050	B
Vest4		0.28
MPC		0.43
ClinPred		0.0054	T
GERP RS		4.4
Varity_R		0.074
gMVP		0.54
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs77172218; hg19: chr1-10428570; COSMIC: COSV99028891; COSMIC: COSV99028891;