rs376759734

Variant names:

• chr2-240740319-C-G
• rs376759734
• NM_001244008.2:c.3795G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-240740319-C-G
• chr2-240740319-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001244008.2(KIF1A):​c.3795G>C​(p.Met1265Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1265L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.776
• 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, G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary spastic paraplegia 30

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2765929).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3795G>C	p.Met1265Ile	missense	Exon 36 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3870G>C	p.Met1290Ile	missense	Exon 36 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3768G>C	p.Met1256Ile	missense	Exon 35 of 49	NP_001366571.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3795G>C	p.Met1265Ile	missense	Exon 36 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000492812.6	TSL:1	n.957G>C		non_coding_transcript_exon	Exon 4 of 16
	KIF1A	ENST00000675932.2		c.3795G>C	p.Met1265Ile	missense	Exon 36 of 49	ENSP00000502786.2	A0A6Q8PHQ5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.78
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.077
Sift	Benign	0.11	T
Sift4G	Benign	0.49	T
Polyphen		0.019	B
Vest4		0.41
MutPred		0.40		Gain of sheet (P = 0.1945)
MVP		0.35
MPC		0.49
ClinPred		0.35	T
GERP RS		2.2
Varity_R		0.14
gMVP		0.34
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376759734; hg19: chr2-241679736;