rs12125492

Variant names:

• chr1-10361820-A-G
• rs12125492
• NM_001365951.3:c.4299A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365951.3(KIF1B):​c.4299A>G​(p.Pro1433Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,702 control chromosomes in the GnomAD database, including 12,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (900 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11681 hom.)
• Consequence: KIF1B NM_001365951.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.302
• Publications: 25 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-10361820-A-G is Benign according to our data. Variant chr1-10361820-A-G is described in ClinVar as Benign. ClinVar VariationId is 129400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.302 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

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.4299A>G	p.Pro1433Pro	synonymous	Exon 40 of 49	NP_001352880.1	O60333-1
	KIF1B	NM_001365952.1		c.4299A>G	p.Pro1433Pro	synonymous	Exon 40 of 49	NP_001352881.1	O60333-1
	KIF1B	NM_015074.3		c.4161A>G	p.Pro1387Pro	synonymous	Exon 38 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.4299A>G	p.Pro1433Pro	synonymous	Exon 40 of 49	ENSP00000502065.1	O60333-1
	KIF1B	ENST00000377081.5	TSL:1	c.4299A>G	p.Pro1433Pro	synonymous	Exon 39 of 48	ENSP00000366284.1	O60333-4
	KIF1B	ENST00000377086.5	TSL:1	c.4299A>G	p.Pro1433Pro	synonymous	Exon 40 of 49	ENSP00000366290.1	O60333-1

Frequencies

GnomAD3 genomes AF: 0.0918 AC: 13967 AN: 152132 Hom.: 901 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.111 AC: 27908 AN: 251006 AF XY: 0.120

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.00413

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.120 AC: 175810 AN: 1461452 Hom.: 11681 Cov.: 33 AF XY: 0.124 AC XY: 89849 AN XY: 727048

African (AFR) AF: 0.0205 AC: 687 AN: 33478

American (AMR) AF: 0.0602 AC: 2693 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5062 AN: 26134

East Asian (EAS) AF: 0.00992 AC: 394 AN: 39700

South Asian (SAS) AF: 0.197 AC: 17032 AN: 86252

European-Finnish (FIN) AF: 0.110 AC: 5815 AN: 53102

Middle Eastern (MID) AF: 0.130 AC: 751 AN: 5768

European-Non Finnish (NFE) AF: 0.123 AC: 136369 AN: 1111902

Other (OTH) AF: 0.116 AC: 7007 AN: 60392

GnomAD4 genome AF: 0.0917 AC: 13964 AN: 152250 Hom.: 900 Cov.: 32 AF XY: 0.0919 AC XY: 6844 AN XY: 74436

African (AFR) AF: 0.0233 AC: 967 AN: 41556

American (AMR) AF: 0.0866 AC: 1325 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 691 AN: 3468

East Asian (EAS) AF: 0.00694 AC: 36 AN: 5186

South Asian (SAS) AF: 0.181 AC: 874 AN: 4816

European-Finnish (FIN) AF: 0.108 AC: 1148 AN: 10606

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8573 AN: 68006

Other (OTH) AF: 0.105 AC: 221 AN: 2114

Alfa AF: 0.110 Hom.: 1770

Bravo AF: 0.0854

Asia WGS AF: 0.0870 AC: 302 AN: 3478

EpiCase AF: 0.126

EpiControl AF: 0.122

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	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
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.8
DANN	Benign	0.62
PhyloP100		-0.30
Mutation Taster		=88/12	polymorphism (auto)

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: rs12125492; hg19: chr1-10421878; COSMIC: COSV55805766; COSMIC: COSV55805766;