2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCCTCCTCCTCCTCC

Variant names:

• chr2-240757423-A-ATCC
• rs10594016
• NM_001244008.2:c.2751_2753dupGGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001244008.2(KIF1A):​c.2751_2753dupGGA​(p.Glu917dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (15 hom., cov: 0)
  • Exomes 𝑓: 0.017 (62 hom.)
• Consequence: KIF1A NM_001244008.2 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.32
• Publications: 17 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001244008.2
• BP6: Variant 2-240757423-A-ATCC is Benign according to our data. Variant chr2-240757423-A-ATCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 497030.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0178 (2448/137632) while in subpopulation AFR AF = 0.0199 (761/38248). AF 95% confidence interval is 0.0187. There are 15 homozygotes in GnomAd4. There are 1140 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.2751_2753dupGGA	p.Glu917dup	disruptive_inframe_insertion	Exon 27 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.2826_2828dupGGA	p.Glu942dup	disruptive_inframe_insertion	Exon 27 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2724_2726dupGGA	p.Glu908dup	disruptive_inframe_insertion	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.2751_2753dupGGA	p.Glu917dup	disruptive_inframe_insertion	Exon 27 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.2751_2753dupGGA	p.Glu917dup	disruptive_inframe_insertion	Exon 27 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.2880_2882dupGGA	p.Glu960dup	disruptive_inframe_insertion	Exon 28 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2450 AN: 137552 Hom.: 15 Cov.: 0

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0163

Gnomad EAS AF: 0.00172

Gnomad SAS AF: 0.0181

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.0137

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0122

GnomAD2 exomes AF: 0.0175 AC: 1927 AN: 110140 AF XY: 0.0178

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00143

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0169 AC: 22675 AN: 1344794 Hom.: 62 Cov.: 0 AF XY: 0.0168 AC XY: 11141 AN XY: 663128

African (AFR) AF: 0.0213 AC: 627 AN: 29372

American (AMR) AF: 0.0117 AC: 397 AN: 33856

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 252 AN: 23930

East Asian (EAS) AF: 0.00149 AC: 51 AN: 34166

South Asian (SAS) AF: 0.0168 AC: 1259 AN: 75054

European-Finnish (FIN) AF: 0.0162 AC: 750 AN: 46340

Middle Eastern (MID) AF: 0.0188 AC: 101 AN: 5376

European-Non Finnish (NFE) AF: 0.0176 AC: 18360 AN: 1040874

Other (OTH) AF: 0.0157 AC: 878 AN: 55826

GnomAD4 genome AF: 0.0178 AC: 2448 AN: 137632 Hom.: 15 Cov.: 0 AF XY: 0.0171 AC XY: 1140 AN XY: 66654

African (AFR) AF: 0.0199 AC: 761 AN: 38248

American (AMR) AF: 0.0119 AC: 160 AN: 13400

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 53 AN: 3256

East Asian (EAS) AF: 0.00172 AC: 8 AN: 4646

South Asian (SAS) AF: 0.0179 AC: 73 AN: 4082

European-Finnish (FIN) AF: 0.0186 AC: 167 AN: 8966

Middle Eastern (MID) AF: 0.0110 AC: 3 AN: 272

European-Non Finnish (NFE) AF: 0.0193 AC: 1200 AN: 62046

Other (OTH) AF: 0.0121 AC: 23 AN: 1900

Alfa AF: 0.0129 Hom.: 1564

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	not specified (2)
-	-	1	KIF1A related neurological disorder (1)
-	-	1	KIF1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=86/14	polymorphism

Splicing

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: rs10594016; hg19: chr2-241696840;