2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCCTCCTCCTCCTCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001244008.2(KIF1A):c.2751_2753dupGGA(p.Glu917dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.018 ( 15 hom., cov: 0)

Exomes 𝑓: 0.017 ( 62 hom. )

Consequence

KIF1A
NM_001244008.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.32

Publications

17 publications found

Variant links:

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

KIF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP3

Nonframeshift variant in repetitive region in NM_001244008.2

BP6

Variant 2-240757423-A-ATCC is Benign according to our data. Variant chr2-240757423-A-ATCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 497030.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0178 (2448/137632) while in subpopulation AFR AF = 0.0199 (761/38248). AF 95% confidence interval is 0.0187. There are 15 homozygotes in GnomAd4. There are 1140 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.2751_2753dupGGA	p.Glu917dup	disruptive_inframe_insertion	Exon 27 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.2751_2753dupGGA	p.Glu917dup	disruptive_inframe_insertion	Exon 27 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2450

AN:

137552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0163

Gnomad EAS

AF:

0.00172

Gnomad SAS

AF:

0.0181

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.0137

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0122

GnomAD2 exomes

AF:

0.0175

AC:

1927

AN:

110140

AF XY:

0.0178

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.0120

Gnomad EAS exome

AF:

0.00143

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0294

GnomAD4 exome

AF:

0.0169

AC:

22675

AN:

1344794

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

11141

AN XY:

663128

show subpopulations

African (AFR)

AF:

0.0213

AC:

627

AN:

29372

American (AMR)

AF:

0.0117

AC:

397

AN:

33856

Ashkenazi Jewish (ASJ)

AF:

0.0105

AC:

252

AN:

23930

East Asian (EAS)

AF:

0.00149

AC:

AN:

34166

South Asian (SAS)

AF:

0.0168

AC:

1259

AN:

75054

European-Finnish (FIN)

AF:

0.0162

AC:

750

AN:

46340

Middle Eastern (MID)

AF:

0.0188

AC:

101

AN:

5376

European-Non Finnish (NFE)

AF:

0.0176

AC:

18360

AN:

1040874

Other (OTH)

AF:

0.0157

AC:

878

AN:

55826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

1227

2454

3681

4908

6135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

706

1412

2118

2824

3530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0178

AC:

2448

AN:

137632

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1140

AN XY:

66654

show subpopulations

African (AFR)

AF:

0.0199

AC:

761

AN:

38248

American (AMR)

AF:

0.0119

AC:

160

AN:

13400

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

AN:

3256

East Asian (EAS)

AF:

0.00172

AC:

AN:

4646

South Asian (SAS)

AF:

0.0179

AC:

AN:

4082

European-Finnish (FIN)

AF:

0.0186

AC:

167

AN:

8966

Middle Eastern (MID)

AF:

0.0110

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0193

AC:

1200

AN:

62046

Other (OTH)

AF:

0.0121

AC:

AN:

1900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

105

209

314

418

523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0129

Hom.:

1564

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Sep 28, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIF1A: BS1, BS2 -

not specified

Benign:2

Dec 16, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KIF1A-related disorder

Benign:1

Jul 11, 2024

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). -

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 1.878% (rs143816642, 761/38,136 alleles, 3 homozygotes in gnomAD v3.1). 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

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=86/14

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over