2-240722483-G-T

Variant names:

• chr2-240722483-G-T
• rs771217469
• NM_001244008.2:c.4638C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001244008.2(KIF1A):​c.4638C>A​(p.Asn1546Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. N1546S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.959
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1523253).

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.4638C>A	p.Asn1546Lys	missense	Exon 43 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.4713C>A	p.Asn1571Lys	missense	Exon 43 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.4638C>A	p.Asn1546Lys	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.4638C>A	p.Asn1546Lys	missense	Exon 43 of 49	ENSP00000438388.1
	KIF1A	ENST00000460788.5	TSL:1	n.1195C>A		non_coding_transcript_exon	Exon 3 of 9
	KIF1A	ENST00000492812.6	TSL:1	n.3221C>A		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395060 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 688084

African (AFR) AF: 0.00 AC: 0 AN: 31532

American (AMR) AF: 0.00 AC: 0 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35856

South Asian (SAS) AF: 0.00 AC: 0 AN: 79138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4414

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078822

Other (OTH) AF: 0.00 AC: 0 AN: 57810

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.94
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.96
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.070
Sift	Benign	0.15	T
Sift4G	Benign	0.54	T
Polyphen		0.090	B
Vest4		0.16
MutPred		0.31		Gain of ubiquitination at N1445 (P = 4e-04)
MVP		0.57
MPC		0.57
ClinPred		0.42	T
GERP RS		-0.12
Varity_R		0.12
gMVP		0.28
Mutation Taster		=78/22	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: rs771217469; hg19: chr2-241661900;