rs1195594601

Variant names:

• chr2-240758372-C-T
• rs1195594601
• NM_001244008.2:c.2570G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001244008.2(KIF1A):​c.2570G>A​(p.Arg857Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,611,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.83

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant in the KIF1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 112 curated pathogenic missense variants (we use a threshold of 10). The gene has 150 curated benign missense variants. Gene score misZ: 5.1579 (above the threshold of 3.09). Trascript score misZ: 5.0191 (above the threshold of 3.09). GenCC associations: The gene is linked to neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2570G>A	p.Arg857Gln	missense_variant	Exon 26 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2570G>A	p.Arg857Gln	missense_variant	Exon 26 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245890 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459362 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725932

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000284 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Uncertain:2

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3B-VUS. Following criteria are met: 0101 - Gain of function is a known mechanism of disease for this gene. 0104 - Mechanism of disease for this gene is dominant negative. 0108 - This gene is known to be associated with both recessive and dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine (exon 25). 0301 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). 0502 - Missense variant with conflicting in-silico predictions and uninformative conservation. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (KIF1B domain; NCBI). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0803 - Low previous evidence of pathogenicity in unrelated individuals. The variant has been previously described as likely pathogenic in a research setting (ClinVar). 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Uncertain:2

Dec 15, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31343797) -

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

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;.;.;.;.;.;.;T;.;.;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	.;N;D;.;.;.;.;.;.;.;.;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.099	.;T;T;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.30	.;T;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.075	B;.;.;.;.;.;.;B;.;.;.;.;D
Vest4		0.70, 0.78
MutPred		0.62		Loss of MoRF binding (P = 0.0575);.;Loss of MoRF binding (P = 0.0575);.;.;Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);.;Loss of MoRF binding (P = 0.0575);.;.;
MVP		0.75
MPC		1.4
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.50
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1195594601; hg19: chr2-241697789;