2-240747320-G-A

Variant names:

• chr2-240747320-G-A
• rs116297894
• NM_001244008.2:c.2979C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.2979C>T​(p.Ala993Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,612,432 control chromosomes in the GnomAD database, including 67 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (36 hom.)
• Consequence: KIF1A NM_001244008.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.000007369
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -1.37

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-240747320-G-A is Benign according to our data. Variant chr2-240747320-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129388.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=7}. Variant chr2-240747320-G-A is described in Lovd as [Benign]. Variant chr2-240747320-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2007/152256) while in subpopulation AFR AF = 0.0449 (1863/41522). AF 95% confidence interval is 0.0432. There are 31 homozygotes in GnomAd4. There are 910 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2979C>T	p.Ala993Ala	splice_region_variant, synonymous_variant	Exon 29 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2979C>T	p.Ala993Ala	splice_region_variant, synonymous_variant	Exon 29 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 2000 AN: 152138 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00383 AC: 947 AN: 247502 AF XY: 0.00289

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00176 AC: 2566 AN: 1460176 Hom.: 36 Cov.: 30 AF XY: 0.00152 AC XY: 1106 AN XY: 726408

Gnomad4 AFR exome AF: 0.0468 AC: 1564 AN: 33416

Gnomad4 AMR exome AF: 0.00195 AC: 87 AN: 44678

Gnomad4 ASJ exome AF: 0.0187 AC: 487 AN: 26088

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39696

Gnomad4 SAS exome AF: 0.0000464 AC: 4 AN: 86188

Gnomad4 FIN exome AF: 0.0000188 AC: 1 AN: 53116

Gnomad4 NFE exome AF: 0.000121 AC: 134 AN: 1110946

Gnomad4 Remaining exome AF: 0.00451 AC: 272 AN: 60294

GnomAD4 genome AF: 0.0132 AC: 2007 AN: 152256 Hom.: 31 Cov.: 33 AF XY: 0.0122 AC XY: 910 AN XY: 74446

Gnomad4 AFR AF: 0.0449 AC: 0.0448678 AN: 0.0448678

Gnomad4 AMR AF: 0.00346 AC: 0.00346315 AN: 0.00346315

Gnomad4 ASJ AF: 0.0167 AC: 0.0167051 AN: 0.0167051

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207297 AN: 0.000207297

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000191 AC: 0.000191126 AN: 0.000191126

Gnomad4 OTH AF: 0.00851 AC: 0.00850662 AN: 0.00850662

Alfa AF: 0.00592 Hom.: 32

Bravo AF: 0.0146

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Dec 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIF1A: BP4, BP7, BS1, BS2 -

Hereditary spastic paraplegia 30 Uncertain:1 Benign:1

Mar 16, 2018

Center for Precision Medicine, Vanderbilt University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:2

Apr 24, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Inborn genetic diseases Benign:1

May 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 13, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.76
DANN	Benign	0.51
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000074
dbscSNV1_RF	Benign	0.0
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: rs116297894; hg19: chr2-241686737;