chr2-240719810-C-T

Variant names:

• chr2-240719810-C-T
• rs199557318
• NM_001244008.2:c.4985G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001244008.2(KIF1A):​c.4985G>A​(p.Arg1662His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,606,608 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1662C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 2.44
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060803175).
• BP6: Variant 2-240719810-C-T is Benign according to our data. Variant chr2-240719810-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464256.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244008.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.4985G>A	p.Arg1662His	missense	Exon 46 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.5060G>A	p.Arg1687His	missense	Exon 46 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.4985G>A	p.Arg1662His	missense	Exon 46 of 49	NP_001366571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.4985G>A	p.Arg1662His	missense	Exon 46 of 49	ENSP00000438388.1
	KIF1A	ENST00000460788.5	TSL:1	n.1542G>A		non_coding_transcript_exon	Exon 6 of 9
	KIF1A	ENST00000492812.6	TSL:1	n.3568G>A		non_coding_transcript_exon	Exon 13 of 16

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000184 AC: 44 AN: 239574 AF XY: 0.000214

Gnomad AFR exome AF: 0.000400

Gnomad AMR exome AF: 0.000446

Gnomad ASJ exome AF: 0.00116

Gnomad EAS exome AF: 0.0000570

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000835

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000155 AC: 225 AN: 1454380 Hom.: 0 Cov.: 30 AF XY: 0.000159 AC XY: 115 AN XY: 723114

African (AFR) AF: 0.000391 AC: 13 AN: 33226

American (AMR) AF: 0.000410 AC: 18 AN: 43944

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 30 AN: 25700

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39488

South Asian (SAS) AF: 0.000106 AC: 9 AN: 85224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52302

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5686

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1108710

Other (OTH) AF: 0.000200 AC: 12 AN: 60100

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74370

African (AFR) AF: 0.000386 AC: 16 AN: 41458

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.000252 AC: 1

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000207 AC: 25

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

May 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the heterozygous state in an adult with hereditary spastic paraplegia (PMID: 32737135); Identified in a healthy parent of an individual with epilepsy and intellectual disability (PMID: 34490037); In silico analysis indicates that this missense variant does not alter protein structure/function; This amino acid substitution does not occur within the predicted motor domain of the protein, where most pathogenic missense variants in KIF1A have been identified (PMID: 25265257); This variant is associated with the following publications: (PMID: 34490037, 32737135, 25265257)

Oct 07, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KIF1A c.4682G>A; p.Arg1561His variant (rs199557318), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 464256). This variant is found in the Ashkenazi Jewish population with an overall allele frequency of 0.11% (11/9766 alleles) in the Genome Aggregation Database. The arginine at codon 1561 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Arg1561His variant is uncertain at this time.

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIF1A: PP2

Sep 10, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary spastic paraplegia 30 Benign:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely 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 Likely benign. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Variants with a dominant negative effect have been shown to cause NESCAV syndrome (MIM#614255; OMIM). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplegia (MIM#610357, MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMID: 31488895, 31455732). (I) 0108 - This gene is associated with both recessive and dominant disease. Genotype-phenotype correlation is not currently established. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2; 57 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; 5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS and likely benign in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - Variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.080
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.10	T
Sift4G	Benign	0.56	T
Polyphen		0.95	P
Vest4		0.51
MVP		0.73
MPC		1.3
ClinPred		0.043	T
GERP RS		4.1
Varity_R		0.090
gMVP		0.23
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs199557318; hg19: chr2-241659227; COSMIC: COSV57502181; COSMIC: COSV57502181;