NM_001244008.2:c.2751G>T

Variant names:

• chr2-240757426-C-A
• rs537608637
• NM_001244008.2:c.2751G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001244008.2(KIF1A):​c.2751G>T​(p.Glu917Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• Publications: 6 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054769307).

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.2751G>T	p.Glu917Asp	missense	Exon 27 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.2826G>T	p.Glu942Asp	missense	Exon 27 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2724G>T	p.Glu908Asp	missense	Exon 26 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.2751G>T	p.Glu917Asp	missense	Exon 27 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.2751G>T	p.Glu917Asp	missense	Exon 27 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.2880G>T	p.Glu960Asp	missense	Exon 28 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 22392 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000421 AC: 9 AN: 213702 Hom.: 0 Cov.: 0 AF XY: 0.0000664 AC XY: 7 AN XY: 105394

African (AFR) AF: 0.00 AC: 0 AN: 578

American (AMR) AF: 0.00 AC: 0 AN: 7182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2342

East Asian (EAS) AF: 0.00 AC: 0 AN: 2118

South Asian (SAS) AF: 0.0000594 AC: 1 AN: 16840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 880

European-Non Finnish (NFE) AF: 0.0000413 AC: 7 AN: 169680

Other (OTH) AF: 0.000129 AC: 1 AN: 7750

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 22392 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11324

African (AFR) AF: 0.00 AC: 0 AN: 830

American (AMR) AF: 0.00 AC: 0 AN: 3300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 474

East Asian (EAS) AF: 0.00 AC: 0 AN: 454

South Asian (SAS) AF: 0.00 AC: 0 AN: 1592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12962

Other (OTH) AF: 0.00 AC: 0 AN: 276

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.97
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.091
Sift	Benign	0.44	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.16		Loss of helix (P = 0.1299)
MVP		0.35
MPC		0.39
ClinPred		0.10	T
GERP RS		3.2
gMVP		0.47
Mutation Taster		=96/4	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: rs537608637; hg19: chr2-241696843; COSMIC: COSV57485284;