2-240758462-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP6

The NM_001244008.2(KIF1A):c.2480G>A(p.Arg827His) variant causes a missense change. The variant allele was found at a frequency of 0.00000825 in 1,455,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R827C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.80

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 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KIF1A
• BP6: Variant 2-240758462-C-T is Benign according to our data. Variant chr2-240758462-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464221.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.2480G>A	p.Arg827His	missense_variant	26/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.2480G>A	p.Arg827His	missense_variant	26/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000837 AC: 2 AN: 238892 Hom.: 0 AF XY: 0.0000154 AC XY: 2 AN XY: 129978

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000342

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000825 AC: 12 AN: 1455350 Hom.: 0 Cov.: 31 AF XY: 0.00000967 AC XY: 7 AN XY: 723540

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000812

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0077	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.;.;.;.;.;.;T;.;.;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
Polyphen		0.20	B;.;.;.;.;.;.;B;.;.;.;.;P
Vest4		0.44, 0.44
MutPred		0.41		Gain of disorder (P = 0.1053);.;Gain of disorder (P = 0.1053);.;.;Gain of disorder (P = 0.1053);Gain of disorder (P = 0.1053);Gain of disorder (P = 0.1053);Gain of disorder (P = 0.1053);.;Gain of disorder (P = 0.1053);.;.;
MVP		0.64
MPC		0.80
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.15
gMVP		0.48

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: rs768899178; hg19: chr2-241697879; COSMIC: COSV100241130;