rs672601368

Variant names:

• chr2-240785062-C-G
• rs672601368
• NM_001244008.2:c.647G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-240785062-C-G
• chr2-240785062-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_001244008.2(KIF1A):​c.647G>C​(p.Arg216Pro) 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. 12/21 in silico tools predict a damaging 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. R216C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.62

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-240785063-G-A is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 2-240785062-C-G is Pathogenic according to our data. Variant chr2-240785062-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162058.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.647G>C	p.Arg216Pro	missense_variant	Exon 7 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.647G>C	p.Arg216Pro	missense_variant	Exon 7 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Pathogenic:2 Uncertain:1

Jan 01, 2014

CHU Sainte-Justine Research Center, University of Montreal

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 15, 2020

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as likely pathogenic for NESCAV syndrome, 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); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); 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); Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5); Assumed de novo, but no confirmation of paternity and maternity (PM6). -

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo in a 7-year-old male with global delays, cerebellar atrophy, optic nerve pallor, mixed tone, epilepsy, ataxia, dysmorphisms, short stature, contractures -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;H;.;.;.;.;.;H;.;.;.;H;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.0	.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;D;.
Vest4		0.98, 0.99
MutPred		0.89		Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);Loss of catalytic residue at R216 (P = 0.0142);
MVP		0.97
MPC		2.8
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.98
gMVP		1.0

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: rs672601368; hg19: chr2-241724479;