rs183359489

Variant names:

• chr2-240746156-C-T
• rs183359489
• NM_001244008.2:c.3085G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001244008.2(KIF1A):​c.3085G>A​(p.Val1029Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,565,742 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1029V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (13 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 2.21
• Publications: 7 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064137876).
• BP6: Variant 2-240746156-C-T is Benign according to our data. Variant chr2-240746156-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245637.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00153 (233/152288) while in subpopulation NFE AF = 0.00256 (174/68006). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD gene

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.3085G>A	p.Val1029Met	missense	Exon 30 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3160G>A	p.Val1054Met	missense	Exon 30 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3058G>A	p.Val1020Met	missense	Exon 29 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.3085G>A	p.Val1029Met	missense	Exon 30 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.3085G>A	p.Val1029Met	missense	Exon 30 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.3214G>A	p.Val1072Met	missense	Exon 31 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00137 AC: 238 AN: 173276 AF XY: 0.00140

Gnomad AFR exome AF: 0.000755

Gnomad AMR exome AF: 0.000761

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000243

Gnomad FIN exome AF: 0.000303

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.00128

GnomAD4 exome AF: 0.00259 AC: 3667 AN: 1413454 Hom.: 13 Cov.: 33 AF XY: 0.00252 AC XY: 1763 AN XY: 698622

African (AFR) AF: 0.000651 AC: 21 AN: 32260

American (AMR) AF: 0.000882 AC: 33 AN: 37432

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25320

East Asian (EAS) AF: 0.0000543 AC: 2 AN: 36854

South Asian (SAS) AF: 0.0000998 AC: 8 AN: 80170

European-Finnish (FIN) AF: 0.000466 AC: 23 AN: 49312

Middle Eastern (MID) AF: 0.00926 AC: 53 AN: 5722

European-Non Finnish (NFE) AF: 0.00314 AC: 3421 AN: 1087770

Other (OTH) AF: 0.00179 AC: 105 AN: 58614

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74462

African (AFR) AF: 0.000650 AC: 27 AN: 41556

American (AMR) AF: 0.00183 AC: 28 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 68006

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00203 Hom.: 1

Bravo AF: 0.00137

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000498 AC: 2

ESP6500EA AF: 0.00264 AC: 22

ExAC AF: 0.000961 AC: 113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	2	not specified (3)
-	-	1	Hereditary ataxia (1)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Hereditary spastic paraplegia 30 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	KIF1A-related disorder (1)
-	-	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	0.087
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.16
Sift	Benign	0.063	T
Sift4G	Benign	0.18	T
Polyphen		0.78	P
Vest4		0.19
MVP		0.57
MPC		0.45
ClinPred		0.016	T
GERP RS		4.0
PromoterAI		0.0040	Neutral
Varity_R		0.082
gMVP		0.34
Mutation Taster		=100/0	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: rs183359489; hg19: chr2-241685573; COSMIC: COSV57495817; COSMIC: COSV57495817;