chr2-240771036-C-A

Position:

• chr2-240771036-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001244008.2(KIF1A):​c.1276G>T​(p.Val426Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.45

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 Uncertain_significance. Variant got 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19669348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.1276G>T	p.Val426Leu	missense_variant	15/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.1276G>T	p.Val426Leu	missense_variant	15/49	5	NM_001244008.2	ENSP00000438388

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	.;T;D;D;D;D;.;D;D;D;D;D;T;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	.;N;N;.;.;.;.;.;.;.;.;.;N;.
REVEL	Benign	0.079
Sift	Benign	0.059	.;T;T;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Benign	0.22	.;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.22	B;.;.;.;.;.;.;B;.;.;.;.;B;.
Vest4		0.41, 0.42
MutPred		0.20		Loss of catalytic residue at V417 (P = 0.1996);.;Loss of catalytic residue at V417 (P = 0.1996);.;.;Loss of catalytic residue at V417 (P = 0.1996);Loss of catalytic residue at V417 (P = 0.1996);Loss of catalytic residue at V417 (P = 0.1996);Loss of catalytic residue at V417 (P = 0.1996);.;Loss of catalytic residue at V417 (P = 0.1996);.;.;.;
MVP		0.45
MPC		1.2
ClinPred		0.43	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.78

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: rs531522772; hg19: chr2-241710453; COSMIC: COSV99064879; COSMIC: COSV99064879;