2-240787287-G-T

Variant names:

• chr2-240787287-G-T
• rs35139906
• NM_001244008.2:c.393C>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.393C>A​(p.Asn131Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N131N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.53

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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25202525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.393C>A	p.Asn131Lys	missense_variant	Exon 5 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.393C>A	p.Asn131Lys	missense_variant	Exon 5 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.63	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.34	N;N;.;.;.;.;.;N;.;.;.;N;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.0	.;D;N;.;.;.;.;.;.;.;.;D;.
REVEL	Uncertain	0.37
Sift	Benign	0.095	.;T;T;.;.;.;.;.;.;.;.;T;.
Sift4G	Benign	0.46	.;T;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.95	P;.;.;.;.;.;.;P;.;.;.;P;.
Vest4		0.61, 0.62
MutPred		0.39		Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);Loss of stability (P = 0.0237);
MVP		0.61
MPC		1.5
ClinPred		0.61	D
GERP RS		-4.3
Varity_R		0.27
gMVP		0.89

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: rs35139906; hg19: chr2-241726704;