2-240723566-G-A

Position:

• chr2-240723566-G-A

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.4319-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00981 in 1,529,832 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (399 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (377 hom.)
• Consequence: KIF1A NM_001244008.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002721
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.00700

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 2-240723566-G-A is Benign according to our data. Variant chr2-240723566-G-A is described in ClinVar as [Benign]. Clinvar id is 129394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240723566-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.4319-8C>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.4319-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.0427 AC: 6490 AN: 152132 Hom.: 400 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0214

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0127 AC: 1986 AN: 155794 Hom.: 101 AF XY: 0.0109 AC XY: 905 AN XY: 82872

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.00789

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.000783

Gnomad SAS exome AF: 0.00714

Gnomad FIN exome AF: 0.0000639

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00972

GnomAD4 exome AF: 0.00618 AC: 8510 AN: 1377582 Hom.: 377 Cov.: 32 AF XY: 0.00579 AC XY: 3907 AN XY: 674736

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.00972

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.00138

Gnomad4 SAS exome AF: 0.00815

Gnomad4 FIN exome AF: 0.0000835

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0427 AC: 6500 AN: 152250 Hom.: 399 Cov.: 33 AF XY: 0.0407 AC XY: 3028 AN XY: 74434

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0214

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0220 Hom.: 87

Bravo AF: 0.0485

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 26, 2015	- -
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. -

not provided Benign:2

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

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Hereditary spastic paraplegia 30 Benign:1

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. -

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

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	4.7
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.070		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: rs1529663; hg19: chr2-241662983;