rs41274456

Positions:

• chr1-10278146-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365951.3(KIF1B):​c.1180+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,611,316 control chromosomes in the GnomAD database, including 1,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (108 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1227 hom.)
• Consequence: KIF1B NM_001365951.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.65

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=-0.82).
• BP6: Variant 1-10278146-C-T is Benign according to our data. Variant chr1-10278146-C-T is described in ClinVar as [Benign]. Clinvar id is 260540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10278146-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0303 (4613/152190) while in subpopulation NFE AF= 0.0454 (3084/67988). AF 95% confidence interval is 0.044. There are 108 homozygotes in gnomad4. There are 2226 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4613 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.1180+18C>T		intron_variant		ENST00000676179.1	NP_001352880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.1180+18C>T		intron_variant			NM_001365951.3	ENSP00000502065	P1

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4614 AN: 152072 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.00640

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0619

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.0584

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0326 AC: 8184 AN: 251288 Hom.: 200 AF XY: 0.0328 AC XY: 4454 AN XY: 135824

Gnomad AFR exome AF: 0.00628

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0610

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0156

Gnomad FIN exome AF: 0.0585

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0386 AC: 56372 AN: 1459126 Hom.: 1227 Cov.: 30 AF XY: 0.0383 AC XY: 27801 AN XY: 726036

Gnomad4 AFR exome AF: 0.00634

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.0597

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.0558

Gnomad4 NFE exome AF: 0.0426

Gnomad4 OTH exome AF: 0.0351

GnomAD4 genome AF: 0.0303 AC: 4613 AN: 152190 Hom.: 108 Cov.: 32 AF XY: 0.0299 AC XY: 2226 AN XY: 74406

Gnomad4 AFR AF: 0.00638

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0619

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0152

Gnomad4 FIN AF: 0.0584

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0406 Hom.: 40

Bravo AF: 0.0270

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs41274456; hg19: chr1-10338204; COSMIC: COSV55805642; COSMIC: COSV55805642;