2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCCTCCTCC

Variant names:

• chr2-240757423-ATCC-A
• rs10594016
• NM_001244008.2:c.2751_2753delGGA

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.2751_2753delGGA​(p.Glu917del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,443,684 control chromosomes in the GnomAD database, including 157,487 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (28069 hom., cov: 0)
  • Exomes 𝑓: 0.51 (129418 hom.)
• Consequence: KIF1A NM_001244008.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.22

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001244008.2
• BP6: Variant 2-240757423-ATCC-A is Benign according to our data. Variant chr2-240757423-ATCC-A is described in ClinVar as [Likely_benign]. Clinvar id is 284274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240757423-ATCC-A is described in Lovd as [Benign]. Variant chr2-240757423-ATCC-A is described in Lovd as [Benign]. Variant chr2-240757423-ATCC-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2751_2753delGGA	p.Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2751_2753delGGA	p.Glu917del	disruptive_inframe_deletion	Exon 27 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.646 AC: 88747 AN: 137280 Hom.: 28022 Cov.: 0

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.637

GnomAD3 exomes AF: 0.525 AC: 57824 AN: 110140 Hom.: 11329 AF XY: 0.518 AC XY: 30944 AN XY: 59702

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.449

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.646

Gnomad SAS exome AF: 0.439

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.508 AC: 663522 AN: 1306324 Hom.: 129418 AF XY: 0.505 AC XY: 324197 AN XY: 642016

Gnomad4 AFR exome AF: 0.725

Gnomad4 AMR exome AF: 0.433

Gnomad4 ASJ exome AF: 0.555

Gnomad4 EAS exome AF: 0.610

Gnomad4 SAS exome AF: 0.418

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.505

Gnomad4 OTH exome AF: 0.522

GnomAD4 genome AF: 0.647 AC: 88841 AN: 137360 Hom.: 28069 Cov.: 0 AF XY: 0.643 AC XY: 42788 AN XY: 66516

Gnomad4 AFR AF: 0.832

Gnomad4 AMR AF: 0.572

Gnomad4 ASJ AF: 0.630

Gnomad4 EAS AF: 0.713

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.635

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Aug 26, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 12, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Hereditary spastic paraplegia 30 Benign:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of spastic paraplegia 30, autosomal recessive (MIM#610357), with 26,739 homozygotes in gnomAD v3. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

KIF1A related neurological disorder Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

African population allele frequency is 75.16% (rs143816642, 57824/110140 alleles, 11329 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

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: rs10594016; hg19: chr2-241696840;