2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCC

Variant names:

• chr2-240757423-ATCCTCCTCC-A
• rs10594016
• NM_001244008.2:c.2745_2753delGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_001244008.2(KIF1A):​c.2745_2753delGGAGGAGGA​(p.Glu915_Glu917del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000107 in 1,482,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: KIF1A NM_001244008.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.36
• 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001244008.2
• BP6: Variant 2-240757423-ATCCTCCTCC-A is Benign according to our data. Variant chr2-240757423-ATCCTCCTCC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1341632.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000349 (48/137634) while in subpopulation AFR AF = 0.000994 (38/38246). AF 95% confidence interval is 0.000744. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 0. 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.2745_2753delGGAGGAGGA	p.Glu915_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.2820_2828delGGAGGAGGA	p.Glu940_Glu942del	disruptive_inframe_deletion	Exon 27 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2718_2726delGGAGGAGGA	p.Glu906_Glu908del	disruptive_inframe_deletion	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.2745_2753delGGAGGAGGA	p.Glu915_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.2745_2753delGGAGGAGGA	p.Glu915_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.2874_2882delGGAGGAGGA	p.Glu958_Glu960del	disruptive_inframe_deletion	Exon 28 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 48 AN: 137554 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000215

Gnomad SAS AF: 0.000244

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000967

Gnomad OTH AF: 0.00106

GnomAD2 exomes AF: 0.000182 AC: 20 AN: 110140 AF XY: 0.000100

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.000279

Gnomad ASJ exome AF: 0.000159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000316

GnomAD4 exome AF: 0.0000818 AC: 110 AN: 1344924 Hom.: 0 AF XY: 0.0000890 AC XY: 59 AN XY: 663212

African (AFR) AF: 0.000851 AC: 25 AN: 29362

American (AMR) AF: 0.000177 AC: 6 AN: 33854

Ashkenazi Jewish (ASJ) AF: 0.0000418 AC: 1 AN: 23928

East Asian (EAS) AF: 0.0000585 AC: 2 AN: 34160

South Asian (SAS) AF: 0.0000799 AC: 6 AN: 75078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46348

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5376

European-Non Finnish (NFE) AF: 0.0000586 AC: 61 AN: 1041002

Other (OTH) AF: 0.000143 AC: 8 AN: 55816

GnomAD4 genome AF: 0.000349 AC: 48 AN: 137634 Hom.: 0 Cov.: 0 AF XY: 0.000300 AC XY: 20 AN XY: 66660

African (AFR) AF: 0.000994 AC: 38 AN: 38246

American (AMR) AF: 0.00 AC: 0 AN: 13400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3258

East Asian (EAS) AF: 0.000215 AC: 1 AN: 4646

South Asian (SAS) AF: 0.000245 AC: 1 AN: 4082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000967 AC: 6 AN: 62048

Other (OTH) AF: 0.00105 AC: 2 AN: 1900

Alfa AF: 0.0000660 Hom.: 1564

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	KIF1A-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=149/51	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs10594016; hg19: chr2-241696840;