2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCCTCCTCC

Variant names:

• chr2-240757423-ATCC-A
• rs10594016
• NM_001244008.2:c.2751_2753delGGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001244008.2(KIF1A):​c.2751_2753delGGA​(p.Glu917del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,443,684 control chromosomes in the GnomAD database, including 157,487 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (28069 hom., cov: 0)
  • Exomes 𝑓: 0.51 (129418 hom.)
• Consequence: KIF1A NM_001244008.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.22
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001244008.2
• BP6: Variant 2-240757423-ATCC-A is Benign according to our data. Variant chr2-240757423-ATCC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

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_2753delGGA	p.Glu917del	disruptive_inframe_deletion	Exon 27 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.2826_2828delGGA	p.Glu942del	disruptive_inframe_deletion	Exon 27 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2724_2726delGGA	p.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.2751_2753delGGA	p.Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.2751_2753delGGA	p.Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.2880_2882delGGA	p.Glu960del	disruptive_inframe_deletion	Exon 28 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.646 AC: 88747 AN: 137280 Hom.: 28022 Cov.: 0

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.637

GnomAD2 exomes AF: 0.525 AC: 57824 AN: 110140 AF XY: 0.518

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.449

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.646

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.508 AC: 663522 AN: 1306324 Hom.: 129418 AF XY: 0.505 AC XY: 324197 AN XY: 642016

African (AFR) AF: 0.725 AC: 21238 AN: 29296

American (AMR) AF: 0.433 AC: 13543 AN: 31290

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 12891 AN: 23218

East Asian (EAS) AF: 0.610 AC: 20320 AN: 33332

South Asian (SAS) AF: 0.418 AC: 28341 AN: 67860

European-Finnish (FIN) AF: 0.504 AC: 22004 AN: 43676

Middle Eastern (MID) AF: 0.544 AC: 2848 AN: 5238

European-Non Finnish (NFE) AF: 0.505 AC: 514083 AN: 1018318

Other (OTH) AF: 0.522 AC: 28254 AN: 54096

GnomAD4 genome AF: 0.647 AC: 88841 AN: 137360 Hom.: 28069 Cov.: 0 AF XY: 0.643 AC XY: 42788 AN XY: 66516

African (AFR) AF: 0.832 AC: 31764 AN: 38200

American (AMR) AF: 0.572 AC: 7645 AN: 13364

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2051 AN: 3256

East Asian (EAS) AF: 0.713 AC: 3310 AN: 4640

South Asian (SAS) AF: 0.459 AC: 1870 AN: 4070

European-Finnish (FIN) AF: 0.554 AC: 4941 AN: 8924

Middle Eastern (MID) AF: 0.629 AC: 171 AN: 272

European-Non Finnish (NFE) AF: 0.571 AC: 35358 AN: 61926

Other (OTH) AF: 0.635 AC: 1204 AN: 1896

Alfa AF: 0.469 Hom.: 1564

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 30 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	KIF1A related neurological disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=92/8	polymorphism (auto)

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: rs10594016; hg19: chr2-241696840; COSMIC: COSV57481902;