NM_001244008.2:c.2269C>G

Variant names:

• chr2-240760840-G-C
• rs369410320
• NM_001244008.2:c.2269C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001244008.2(KIF1A):​c.2269C>G​(p.Gln757Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,605,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 7.41
• 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 0 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-240760840-G-C is Benign according to our data. Variant chr2-240760840-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432631.

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.2269C>G	p.Gln757Glu	missense	Exon 25 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.2344C>G	p.Gln782Glu	missense	Exon 25 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2242C>G	p.Gln748Glu	missense	Exon 24 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.2269C>G	p.Gln757Glu	missense	Exon 25 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.2269C>G	p.Gln757Glu	missense	Exon 25 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.2398C>G	p.Gln800Glu	missense	Exon 26 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000418 AC: 10 AN: 239296 AF XY: 0.0000537

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000823

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000255 AC: 370 AN: 1453620 Hom.: 0 Cov.: 31 AF XY: 0.000224 AC XY: 162 AN XY: 722946

African (AFR) AF: 0.00 AC: 0 AN: 33062

American (AMR) AF: 0.0000465 AC: 2 AN: 42986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39068

South Asian (SAS) AF: 0.00 AC: 0 AN: 84468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.000329 AC: 365 AN: 1109136

Other (OTH) AF: 0.0000500 AC: 3 AN: 60022

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74390

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000414 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.19
Sift	Benign	0.12	T
Sift4G	Benign	0.51	T
Polyphen		0.0030	B
Vest4		0.41
MVP		0.68
MPC		0.50
ClinPred		0.15	T
GERP RS		4.3
Varity_R		0.19
gMVP		0.44
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.54		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369410320; hg19: chr2-241700257;