rs786200949

chr2-240788208-G-Achr2-240788208-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_001244008.2(KIF1A):c.206C>T(p.Ser69Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S69W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.22

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 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 chr2-240788208-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 989188.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, KIF1A
• PP5: Variant 2-240788208-G-A is Pathogenic according to our data. Variant chr2-240788208-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240788208-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.206C>T	p.Ser69Leu	missense_variant	4/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.206C>T	p.Ser69Leu	missense_variant	4/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 30 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 14, 2015	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jun 15, 2020	This variant is interpreted as likely pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to moderate); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1 moderate); Assumed de novo, but no confirmation of paternity and maternity (PM6); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Neuromuscular disorders lab, University of Helsinki

Oct 27, 2014

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2022

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188057). This missense change has been observed in individual(s) with uncomplicated hereditary spastic paraplegia (PMID: 25585697, 26410750). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 69 of the KIF1A protein (p.Ser69Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.;.;M;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
Polyphen		0.96	D;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.90, 0.76
MutPred		0.40		Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);Loss of disorder (P = 0.0106);
MVP		0.84
MPC		1.5
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.43
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs786200949; hg19: chr2-241727625;