rs62637652

Positions:

• chr2-240760724-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.2385C>T​(p.Ala795Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,588,182 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 33)
  • Exomes 𝑓: 0.014 (177 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.99

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]

KIF1A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-240760724-G-A is Benign according to our data. Variant chr2-240760724-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240760724-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00968 (1475/152310) while in subpopulation NFE AF= 0.014 (953/68034). AF 95% confidence interval is 0.0133. There are 12 homozygotes in gnomad4. There are 759 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2385C>T	p.Ala795Ala	synonymous_variant	25/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2385C>T	p.Ala795Ala	synonymous_variant	25/49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.00969 AC: 1475 AN: 152192 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.0118 AC: 2624 AN: 223078 Hom.: 27 AF XY: 0.0121 AC XY: 1482 AN XY: 122168

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00459

Gnomad EAS exome AF: 0.000128

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0143 AC: 20590 AN: 1435872 Hom.: 177 Cov.: 31 AF XY: 0.0142 AC XY: 10138 AN XY: 711736

Gnomad4 AFR exome AF: 0.00213

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.0000789

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.0295

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.00968 AC: 1475 AN: 152310 Hom.: 12 Cov.: 33 AF XY: 0.0102 AC XY: 759 AN XY: 74478

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.0284

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.0114 Hom.: 8

Bravo AF: 0.00760

Asia WGS AF: 0.00433 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 16, 2021	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KIF1A: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2016

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. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 11, 2021

- -

Hereditary spastic paraplegia 30 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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	-0.45
CADD	Benign	1.8
DANN	Benign	0.91

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: rs62637652; hg19: chr2-241700141;