rs56024577

chr2-240741385-G-Achr2-240741385-G-Cchr2-240741385-G-T

Variant summary

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

The NM_001244008.2(KIF1A):c.3641-8C>T variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.279 in 1,543,814 control chromosomes in the GnomAD database, including 66,318 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5486 hom., cov: 33)
  • Exomes 𝑓: 0.28 (60832 hom.)
• Consequence: KIF1A NM_001244008.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003042
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.72

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-240741385-G-A is Benign according to our data. Variant chr2-240741385-G-A is described in ClinVar as [Benign]. Clinvar id is 129391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240741385-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.3641-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.3641-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35771 AN: 152008 Hom.: 5473 Cov.: 33

Gnomad AFR AF: 0.0604

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.240

GnomAD3 exomes AF: 0.347 AC: 57808 AN: 166444 Hom.: 11293 AF XY: 0.352 AC XY: 31512 AN XY: 89606

Gnomad AFR exome AF: 0.0590

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.453

Gnomad SAS exome AF: 0.483

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.284 AC: 395390 AN: 1391688 Hom.: 60832 Cov.: 30 AF XY: 0.291 AC XY: 199666 AN XY: 686874

Gnomad4 AFR exome AF: 0.0524

Gnomad4 AMR exome AF: 0.482

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.424

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.235 AC: 35797 AN: 152126 Hom.: 5486 Cov.: 33 AF XY: 0.247 AC XY: 18348 AN XY: 74372

Gnomad4 AFR AF: 0.0603

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.484

Gnomad4 FIN AF: 0.335

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.248

Alfa AF: 0.202 Hom.: 698

Bravo AF: 0.227

Asia WGS AF: 0.438 AC: 1519 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia 30 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Neuropathy, hereditary sensory, type 2C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Intellectual disability, autosomal dominant 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	5.8
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.0080
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: rs56024577; hg19: chr2-241680802; COSMIC: COSV57484858; COSMIC: COSV57484858;