2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCCTCC

Variant names:

• chr2-240757423-ATCCTCC-A
• rs10594016
• NM_001244008.2:c.2748_2753delGGAGGA

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.2748_2753delGGAGGA​(p.Glu916_Glu917del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0171 in 1,355,642 control chromosomes in the GnomAD database, including 153 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (17 hom., cov: 0)
  • Exomes 𝑓: 0.017 (136 hom.)
• Consequence: KIF1A NM_001244008.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• 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: Benign. The variant received -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001244008.2
• BP6: Variant 2-240757423-ATCCTCC-A is Benign according to our data. Variant chr2-240757423-ATCCTCC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211282.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0147 (2022/137566) while in subpopulation AFR AF = 0.0181 (690/38226). AF 95% confidence interval is 0.0169. There are 17 homozygotes in GnomAd4. There are 941 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.2748_2753delGGAGGA	p.Glu916_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.2823_2828delGGAGGA	p.Glu941_Glu942del	disruptive_inframe_deletion	Exon 27 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2721_2726delGGAGGA	p.Glu907_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.2748_2753delGGAGGA	p.Glu916_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.2748_2753delGGAGGA	p.Glu916_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.2877_2882delGGAGGA	p.Glu959_Glu960del	disruptive_inframe_deletion	Exon 28 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2021 AN: 137486 Hom.: 18 Cov.: 0

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.00770

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00536

Gnomad SAS AF: 0.00659

Gnomad FIN AF: 0.00581

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.00954

GnomAD2 exomes AF: 0.0187 AC: 2065 AN: 110140 AF XY: 0.0190

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.0102

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0173 AC: 21099 AN: 1218076 Hom.: 136 AF XY: 0.0171 AC XY: 10284 AN XY: 600892

African (AFR) AF: 0.0274 AC: 616 AN: 22476

American (AMR) AF: 0.00792 AC: 249 AN: 31420

Ashkenazi Jewish (ASJ) AF: 0.0200 AC: 416 AN: 20780

East Asian (EAS) AF: 0.00516 AC: 144 AN: 27932

South Asian (SAS) AF: 0.00874 AC: 616 AN: 70482

European-Finnish (FIN) AF: 0.00602 AC: 249 AN: 41376

Middle Eastern (MID) AF: 0.00506 AC: 25 AN: 4936

European-Non Finnish (NFE) AF: 0.0190 AC: 17994 AN: 948758

Other (OTH) AF: 0.0158 AC: 790 AN: 49916

GnomAD4 genome AF: 0.0147 AC: 2022 AN: 137566 Hom.: 17 Cov.: 0 AF XY: 0.0141 AC XY: 941 AN XY: 66620

African (AFR) AF: 0.0181 AC: 690 AN: 38226

American (AMR) AF: 0.00769 AC: 103 AN: 13396

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 43 AN: 3258

East Asian (EAS) AF: 0.00517 AC: 24 AN: 4646

South Asian (SAS) AF: 0.00661 AC: 27 AN: 4082

European-Finnish (FIN) AF: 0.00581 AC: 52 AN: 8954

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.0166 AC: 1029 AN: 62018

Other (OTH) AF: 0.00948 AC: 18 AN: 1898

Alfa AF: 0.0467 Hom.: 1564

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	Intellectual disability, autosomal dominant 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=165/35	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; COSMIC: COSV57483139;