rs768899178

Variant names:

• chr2-240758462-C-A
• rs768899178
• NM_001244008.2:c.2480G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240758462-C-A
• chr2-240758462-C-G
• chr2-240758462-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001244008.2(KIF1A):​c.2480G>T​(p.Arg827Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,354 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R827H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.80
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2480G>T	p.Arg827Leu	missense_variant	Exon 26 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2480G>T	p.Arg827Leu	missense_variant	Exon 26 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455354 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723542

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39424

South Asian (SAS) AF: 0.00 AC: 0 AN: 85084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108906

Other (OTH) AF: 0.0000167 AC: 1 AN: 60054

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.;.;.;.;.;T;.;.;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;M;.;.;.;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	.;D;D;.;.;.;.;.;.;.;.;.;D
REVEL	Uncertain	0.49
Sift	Benign	0.21	.;T;T;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.30	.;T;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.99	D;.;.;.;.;.;.;D;.;.;.;.;D
Vest4		0.86, 0.92
MutPred		0.46		Loss of disorder (P = 0.034);.;Loss of disorder (P = 0.034);.;.;Loss of disorder (P = 0.034);Loss of disorder (P = 0.034);Loss of disorder (P = 0.034);Loss of disorder (P = 0.034);.;Loss of disorder (P = 0.034);.;.;
MVP		0.67
MPC		1.2
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.46
gMVP		0.62
Mutation Taster		=26/74	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: rs768899178; hg19: chr2-241697879;