rs373891682

chr2-240766948-C-Gchr2-240766948-C-T

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.1651G>C(p.Val551Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V551I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.499

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 where missense usually causes diseases, KIF1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.116684705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.1651G>C	p.Val551Leu	missense_variant	19/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.1651G>C	p.Val551Leu	missense_variant	19/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246170 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459724 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.36	T;.;.;.;.;.;.;T;.;.;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.50	N
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.17	N;.;.;.;.;.;.;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
Polyphen		0.0	B;.;.;.;.;.;.;B;.;.;.;.;B
Vest4		0.17, 0.082
MutPred		0.45		Gain of catalytic residue at V542 (P = 0.001);.;Gain of catalytic residue at V542 (P = 0.001);.;.;Gain of catalytic residue at V542 (P = 0.001);Gain of catalytic residue at V542 (P = 0.001);Gain of catalytic residue at V542 (P = 0.001);Gain of catalytic residue at V542 (P = 0.001);.;Gain of catalytic residue at V542 (P = 0.001);.;.;
MVP		0.40
MPC		1.2
ClinPred		0.077	T
GERP RS		-0.095
Varity_R		0.15
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373891682; hg19: chr2-241706365;