2-240720969-G-C

Variant names:

• chr2-240720969-G-C
• rs916993059
• NM_001244008.2:c.4813C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001244008.2(KIF1A):​c.4813C>G​(p.Pro1605Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,000 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: 0.0000014 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.4813C>G	p.Pro1605Ala	missense_variant	Exon 45 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.4813C>G	p.Pro1605Ala	missense_variant	Exon 45 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453000 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 721840

Gnomad4 AFR exome AF: 0.0000299

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: 9.02e-7

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

Jun 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1504 of the KIF1A protein (p.Pro1504Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1422803). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KIF1A protein function with a negative predictive value of 95%. 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	.;D;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.12	.;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.17	.;T;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.92	P;.;.;.;.;.;.;P;.;.;.;.;.;.
Vest4		0.61
MutPred		0.24		Loss of glycosylation at P1504 (P = 0.0369);.;.;.;.;.;.;Loss of glycosylation at P1504 (P = 0.0369);.;.;.;.;.;.;
MVP		0.62
MPC		1.3
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.18
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs916993059; hg19: chr2-241660386;