chr2-240785068-C-T

Position:

• chr2-240785068-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001244008.2(KIF1A):​c.641G>A​(p.Ser214Asn) 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 (★). Synonymous variant affecting the same amino acid position (i.e. S214S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 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, 4 uncertain in NM_001244008.2
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.976
• PP5: Variant 2-240785068-C-T is Pathogenic according to our data. Variant chr2-240785068-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521717.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.641G>A	p.Ser214Asn	missense_variant	7/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.641G>A	p.Ser214Asn	missense_variant	7/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;.;.;.;.;.;H;.;.;.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.5	.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;D;.
Vest4		0.90, 0.93
MutPred		0.92		Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);Loss of catalytic residue at S214 (P = 0.0698);
MVP		0.91
MPC		2.1
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.93
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: rs1553638309; hg19: chr2-241724485;