2-240719906-C-T

Variant names:

• chr2-240719906-C-T
• rs191428830
• NM_001244008.2:c.4889G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001244008.2(KIF1A):​c.4889G>A​(p.Arg1630Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,610,628 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1630W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (8 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 3.76
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hereditary spastic paraplegia 30

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PEHO syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006158352).
• BP6: Variant 2-240719906-C-T is Benign according to our data. Variant chr2-240719906-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 335256.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00219 (334/152272) while in subpopulation EAS AF = 0.000964 (5/5186). AF 95% confidence interval is 0.000495. There are 5 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.4889G>A	p.Arg1630Gln	missense_variant	Exon 46 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.4889G>A	p.Arg1630Gln	missense_variant	Exon 46 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 334 AN: 152156 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00257 AC: 628 AN: 243946 AF XY: 0.00262

Gnomad AFR exome AF: 0.000264

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00129 AC: 1880 AN: 1458356 Hom.: 8 Cov.: 30 AF XY: 0.00130 AC XY: 943 AN XY: 725450

African (AFR) AF: 0.000120 AC: 4 AN: 33402

American (AMR) AF: 0.0000224 AC: 1 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26026

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39642

South Asian (SAS) AF: 0.000465 AC: 40 AN: 86042

European-Finnish (FIN) AF: 0.0176 AC: 917 AN: 52176

Middle Eastern (MID) AF: 0.000392 AC: 2 AN: 5104

European-Non Finnish (NFE) AF: 0.000681 AC: 757 AN: 1111196

Other (OTH) AF: 0.000980 AC: 59 AN: 60196

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152272 Hom.: 5 Cov.: 33 AF XY: 0.00328 AC XY: 244 AN XY: 74452

African (AFR) AF: 0.000265 AC: 11 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0253 AC: 269 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000480 Hom.: 0

Bravo AF: 0.000427

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.000719 AC: 6

ExAC AF: 0.00225 AC: 271

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000892

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 17, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the KIF1A gene. The R1529Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1529Q variant was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project but the 1000 Genomes Project reports R1529Q was observed in 8/198 (4.0%) alleles from individuals of Finnish background, indicating it may be a rare (benign) variant in this population. The R1529Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, this amino acid substitution does not occur within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to-date (Lee et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Hereditary spastic paraplegia 30 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1

Nov 08, 2018

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. -

KIF1A-related disorder Benign:1

Jul 12, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 29, 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
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;.;D;D;D;D;D;D;D
MetaRNN	Benign	0.0062	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.;M;.;.;.;.;.;.
PhyloP100		3.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	.;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.062
Sift	Benign	0.22	.;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.64	.;T;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.94	P;.;.;.;.;.;.;P;.;.;.;.;.;.
Vest4		0.34
MVP		0.55
MPC		1.0
ClinPred		0.048	T
GERP RS		4.2
Varity_R		0.14
gMVP		0.42
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs191428830; hg19: chr2-241659323; COSMIC: COSV57494190; COSMIC: COSV57494190;