NM_001365951.3:c.608+8dupA

Variant names:

• chr1-10267565-T-TA
• rs139613776
• NM_001365951.3:c.608+8dupA

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001365951.3(KIF1B):​c.608+8dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,613,808 control chromosomes in the GnomAD database, including 576 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (41 hom., cov: 32)
  • Exomes 𝑓: 0.024 (535 hom.)
• Consequence: KIF1B NM_001365951.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.15
• Publications: 1 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 1-10267565-T-TA is Benign according to our data. Variant chr1-10267565-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220468.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 = 0.0187 (2854/152272) while in subpopulation NFE AF = 0.0279 (1898/68024). AF 95% confidence interval is 0.0269. There are 41 homozygotes in GnomAd4. There are 1425 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2854 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.608+8dupA		intron	N/A	NP_001352880.1	O60333-1
	KIF1B	NM_001365952.1		c.608+8dupA		intron	N/A	NP_001352881.1	O60333-1
	KIF1B	NM_015074.3		c.608+8dupA		intron	N/A	NP_055889.2	O60333-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	ENST00000676179.1	MANE Select	c.608+7_608+8insA		splice_region intron	N/A	ENSP00000502065.1	O60333-1
	KIF1B	ENST00000377081.5	TSL:1	c.608+7_608+8insA		splice_region intron	N/A	ENSP00000366284.1	O60333-4
	KIF1B	ENST00000377086.5	TSL:1	c.608+7_608+8insA		splice_region intron	N/A	ENSP00000366290.1	O60333-1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2854 AN: 152154 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0184 AC: 4615 AN: 251268 AF XY: 0.0181

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.00971

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0426

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0240 AC: 35066 AN: 1461536 Hom.: 535 Cov.: 32 AF XY: 0.0235 AC XY: 17069 AN XY: 727074

African (AFR) AF: 0.00302 AC: 101 AN: 33472

American (AMR) AF: 0.00937 AC: 419 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00658 AC: 172 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.00223 AC: 192 AN: 86248

European-Finnish (FIN) AF: 0.0404 AC: 2158 AN: 53402

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0277 AC: 30801 AN: 1111746

Other (OTH) AF: 0.0200 AC: 1205 AN: 60366

GnomAD4 genome AF: 0.0187 AC: 2854 AN: 152272 Hom.: 41 Cov.: 32 AF XY: 0.0191 AC XY: 1425 AN XY: 74440

African (AFR) AF: 0.00464 AC: 193 AN: 41556

American (AMR) AF: 0.0141 AC: 216 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.0442 AC: 469 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0279 AC: 1898 AN: 68024

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.0216 Hom.: 9

Bravo AF: 0.0156

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0223

EpiControl AF: 0.0245

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	KIF1B-related disorder (1)
-	-	1	Neuroblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139613776; hg19: chr1-10327623;