2-240763259-G-T

Position:

• chr2-240763259-G-T

Variant summary

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

The NM_001244008.2(KIF1A):​c.1856C>A​(p.Ala619Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.62

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.1856C>A	p.Ala619Glu	missense_variant	21/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.1856C>A	p.Ala619Glu	missense_variant	21/49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459726 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 610 of the KIF1A protein (p.Ala610Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF1A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;.;.;.;.;.;.;T;.;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	.;D;D;.;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.43
Sift	Benign	0.15	.;T;T;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.16	.;T;T;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;.;D
Vest4		0.56, 0.61
MutPred		0.19		Gain of solvent accessibility (P = 0.0854);.;Gain of solvent accessibility (P = 0.0854);.;.;Gain of solvent accessibility (P = 0.0854);Gain of solvent accessibility (P = 0.0854);Gain of solvent accessibility (P = 0.0854);Gain of solvent accessibility (P = 0.0854);.;Gain of solvent accessibility (P = 0.0854);.;.;
MVP		0.68
MPC		2.5
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.44
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs765812659; hg19: chr2-241702676;