rs749718096

Variant names:

• chr2-240775862-C-A
• rs749718096
• NM_001244008.2:c.947G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240775862-C-A
• chr2-240775862-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001244008.2(KIF1A):​c.947G>T​(p.Arg316Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R316Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.98
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hereditary spastic paraplegia 30

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PEHO syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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, 9 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 chr2-240775862-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373642.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.947G>T	p.Arg316Leu	missense_variant	Exon 11 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.947G>T	p.Arg316Leu	missense_variant	Exon 11 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	.;T;T;T;T;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.;.;M;.;.;.;.;M;.
PhyloP100		6.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.1	.;D;D;.;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	.;D;D;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.0030	.;D;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;.;D;.
Vest4		0.83, 0.86
MutPred		0.73		Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);.;Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);
MVP		0.78
MPC		2.6
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		-0.0022	Neutral
Varity_R		0.91
gMVP		0.99
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs749718096; hg19: chr2-241715279; COSMIC: COSV100239902; COSMIC: COSV100239902;