rs200184619

Variant names:

• chr2-240722509-G-A
• rs200184619
• NM_001244008.2:c.4612C>T
• KIF1A p.Arg1538Cys

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001244008.2(KIF1A):​c.4612C>T​(p.Arg1538Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,548,000 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1538H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.67
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• hereditary spastic paraplegia 30

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004927784).
• BP6: Variant 2-240722509-G-A is Benign according to our data. Variant chr2-240722509-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464253.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00141 (214/152242) while in subpopulation AFR AF = 0.00455 (189/41544). AF 95% confidence interval is 0.00402. There are 0 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.4612C>T	p.Arg1538Cys	missense	Exon 43 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.4687C>T	p.Arg1563Cys	missense	Exon 43 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.4612C>T	p.Arg1538Cys	missense	Exon 43 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.4612C>T	p.Arg1538Cys	missense	Exon 43 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000460788.5	TSL:1	n.1169C>T		non_coding_transcript_exon	Exon 3 of 9
	KIF1A	ENST00000492812.6	TSL:1	n.3195C>T		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000552 AC: 83 AN: 150482 AF XY: 0.000472

Gnomad AFR exome AF: 0.00428

Gnomad AMR exome AF: 0.000285

Gnomad ASJ exome AF: 0.00394

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000698

Gnomad OTH exome AF: 0.00141

GnomAD4 exome AF: 0.000232 AC: 324 AN: 1395758 Hom.: 0 Cov.: 32 AF XY: 0.000219 AC XY: 151 AN XY: 688448

African (AFR) AF: 0.00422 AC: 133 AN: 31546

American (AMR) AF: 0.000281 AC: 10 AN: 35620

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 100 AN: 25144

East Asian (EAS) AF: 0.00 AC: 0 AN: 35854

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47266

Middle Eastern (MID) AF: 0.000218 AC: 1 AN: 4588

European-Non Finnish (NFE) AF: 0.0000324 AC: 35 AN: 1078774

Other (OTH) AF: 0.000709 AC: 41 AN: 57820

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74432

African (AFR) AF: 0.00455 AC: 189 AN: 41544

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67996

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00179

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Hereditary spastic paraplegia 30 (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	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.076
Sift	Benign	0.078	T
Sift4G	Benign	0.19	T
Varity_R		0.068
gMVP		0.26
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200184619;

hg19: chr2-241661926;

COSMIC: COSV107338420;