2-240783764-G-T

Position:

• chr2-240783764-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001244008.2(KIF1A):​c.773C>A​(p.Thr258Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T258M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.69

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001244008.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-240783764-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, KIF1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 2-240783764-G-T is Pathogenic according to our data. Variant chr2-240783764-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1507070.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.773C>A	p.Thr258Lys	missense_variant	8/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.773C>A	p.Thr258Lys	missense_variant	8/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431030 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708762

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic: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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 21, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr258 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28970574, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt KIF1A protein function. This variant has not been reported in the literature in individuals with KIF1A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 258 of the KIF1A protein (p.Thr258Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.4	M;M;.;.;.;.;.;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
Polyphen		0.82	P;.;.;.;.;.;.;P;.;.;.;P;.
Vest4		0.81, 0.85
MutPred		0.62		Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);
MVP		0.91
MPC		2.2
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.91
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-241723181;