1-10268280-C-T

Position:

• chr1-10268280-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365951.3(KIF1B):​c.720+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,493,890 control chromosomes in the GnomAD database, including 63,411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5373 hom., cov: 31)
  • Exomes 𝑓: 0.29 (58038 hom.)
• Consequence: KIF1B NM_001365951.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.56

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-10268280-C-T is Benign according to our data. Variant chr1-10268280-C-T is described in ClinVar as [Benign]. Clinvar id is 260542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10268280-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3	c.720+17C>T		intron_variant		ENST00000676179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1	c.720+17C>T		intron_variant			NM_001365951.3	P1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38990 AN: 151908 Hom.: 5356 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.282 AC: 70135 AN: 248986 Hom.: 10137 AF XY: 0.279 AC XY: 37491 AN XY: 134552

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.291

Gnomad SAS exome AF: 0.230

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.292 AC: 391352 AN: 1341862 Hom.: 58038 Cov.: 20 AF XY: 0.290 AC XY: 195281 AN XY: 673870

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.341

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.256

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.257 AC: 39040 AN: 152028 Hom.: 5373 Cov.: 31 AF XY: 0.258 AC XY: 19141 AN XY: 74300

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.321

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.285

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.272

Alfa AF: 0.242 Hom.: 1521

Bravo AF: 0.257

Asia WGS AF: 0.275 AC: 955 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 2020	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Pheochromocytoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease type 2A1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.5
DANN	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs1339458; hg19: chr1-10328338; COSMIC: COSV55802811;