chr2-240775862-C-T

Position:

chr2-240775862-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3PP5

The NM_001244008.2(KIF1A):c.947G>A(p.Arg316Gln) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R316W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 5.98

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240775863-G-A is described in Lovd as [Pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.787

PP5

Variant 2-240775862-C-T is Pathogenic according to our data. Variant chr2-240775862-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373642.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Uncertain_significance=2}. Variant chr2-240775862-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.947G>A	p.Arg316Gln	missense_variant	11/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.947G>A	p.Arg316Gln	missense_variant	11/49	5	NM_001244008.2	ENSP00000438388		Q12756-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456578

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725102

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2016	An R316Q variant that is likely pathogenic has been identified in the KIF1A gene. The R316Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a missense variant at the same residue (R316W) has been previously reported as a de novo substituion in an individual with mild intellectual disability, ataxia, optic nerve atrophy, cerebellar atrophy, neuropathy, and spastic paraparesis (Lee et al., 2014). The R316Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R316Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, this amino acid substitution occurs within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to-date (Lee et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

Jul 20, 2021

The c.947G>A (p.Arg316Gln) variant in the KIF1A gene has not been described in the literature to our knowledge. This variant is not present in the population database (GnomAD and ABraOM), suggesting it is not a common benign variant in these populations. This variant is deposited in the ClinVar, but there is a conflict of interpretation (Variation ID: 373642), 1 star. This variant replaces arginine with glutamine at codon 316 of the KIF1A protein, which is highly conserved across different species. This variant is in an important functional domain of the protein (Kinesin motor domain). Additionally, a missense variant in the same amino acid (p.Arg316Trp) was described in two unrelated patients with a complex clinical picture characterized by global developmental delay, moderate to severe intellectual disability, optic nerve atrophy, cerebellar atrophy, ataxia, and spastic paraparesis (PMID: 25265257; PMID: 26354034). Our lab found it once, in heterozygous, in a 4-years-old female with a complex CMT2 phenotype. In summary, the p.Arg316Gln meets our criteria to be classified as likely pathogenic. -

Hereditary spastic paraplegia 30

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Paris Brain Institute, Inserm - ICM

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg316 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25265257, 26125038, 26354034, 28554332). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 373642). This missense change has been observed in individual(s) with clinical features of autosomal dominant hereditary spastic paraplegia (PMID: 32935419, 33880452). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 316 of the KIF1A protein (p.Arg316Gln). -

Spastic paraplegia

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Baylor Genetics

Sep 01, 2017

Likely pathogenicity based on finding it once in our laboratory de novo in an 8-year-old female with progressive lower extremity weakness, spastic paraplegia, neurogenic bowel and bladder (onset at 4y) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.;.;.;.;.;.;D;.;.;.;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

.;D;D;D;D;D;.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

-0.89

N;N;.;.;.;.;.;N;.;.;.;.;N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.4

.;D;D;.;.;.;.;.;.;.;.;.;D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

.;D;D;.;.;.;.;.;.;.;.;.;D;.

Sift4G

Uncertain

0.0060

.;D;D;.;.;.;.;.;.;.;.;.;.;.

Polyphen

1.0

D;.;.;.;.;.;.;D;.;.;.;.;D;.

Vest4

0.72, 0.72

MutPred

0.70

Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);.;Loss of MoRF binding (P = 0.084);Loss of MoRF binding (P = 0.084);

MVP

0.75

MPC

2.6

ClinPred

0.92

GERP RS

4.3

Varity_R

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over