chr2-240722608-C-A

Variant names:

• chr2-240722608-C-A
• rs915433180
• NM_001244008.2:c.4513G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001244008.2(KIF1A):​c.4513G>T​(p.Ala1505Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,411,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. A1505T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.265
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02582702).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244008.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.4513G>T	p.Ala1505Ser	missense	Exon 43 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.4588G>T	p.Ala1530Ser	missense	Exon 43 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.4513G>T	p.Ala1505Ser	missense	Exon 43 of 49	NP_001366571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.4513G>T	p.Ala1505Ser	missense	Exon 43 of 49	ENSP00000438388.1
	KIF1A	ENST00000460788.5	TSL:1	n.1070G>T		non_coding_transcript_exon	Exon 3 of 9
	KIF1A	ENST00000492812.6	TSL:1	n.3096G>T		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1411354 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 697002

African (AFR) AF: 0.00 AC: 0 AN: 32334

American (AMR) AF: 0.00 AC: 0 AN: 38668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 37334

South Asian (SAS) AF: 0.00 AC: 0 AN: 80176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4974

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085584

Other (OTH) AF: 0.00 AC: 0 AN: 58232

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.070
DANN	Benign	0.52
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.27
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.083
Sift	Benign	0.85	T
Sift4G	Benign	0.73	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.20		Gain of phosphorylation at A1404 (P = 0.0187)
MVP		0.19
MPC		0.39
ClinPred		0.064	T
GERP RS		-2.8
Varity_R		0.035
gMVP		0.39
Mutation Taster		=98/2	polymorphism

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: rs915433180; hg19: chr2-241662025;