rs116297894

Variant names:

• chr2-240747320-G-A
• rs116297894
• NM_001244008.2:c.2979C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240747320-G-A
• chr2-240747320-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BS1 BS2

The NM_001379631.1(KIF1A):​c.3054C>T​(p.Ala1018Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,612,432 control chromosomes in the GnomAD database, including 67 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (36 hom.)
• Consequence: KIF1A NM_001379631.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.000007369
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -1.37
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hereditary spastic paraplegia 30

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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.

• BP6: Variant 2-240747320-G-A is Benign according to our data. Variant chr2-240747320-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129388.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2007/152256) while in subpopulation AFR AF = 0.0449 (1863/41522). AF 95% confidence interval is 0.0432. There are 31 homozygotes in GnomAd4. There are 910 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379631.1. 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.2979C>T	p.Ala993Ala	splice_region synonymous	Exon 29 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.3054C>T	p.Ala1018Ala	splice_region synonymous	Exon 29 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2952C>T	p.Ala984Ala	splice_region synonymous	Exon 28 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.2979C>T	p.Ala993Ala	splice_region synonymous	Exon 29 of 49	ENSP00000438388.1
	KIF1A	ENST00000675932.2		c.2979C>T	p.Ala993Ala	splice_region synonymous	Exon 29 of 49	ENSP00000502786.2
	KIF1A	ENST00000675314.2		c.3108C>T	p.Ala1036Ala	splice_region synonymous	Exon 30 of 50	ENSP00000502584.2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 2000 AN: 152138 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00383 AC: 947 AN: 247502 AF XY: 0.00289

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00176 AC: 2566 AN: 1460176 Hom.: 36 Cov.: 30 AF XY: 0.00152 AC XY: 1106 AN XY: 726408

African (AFR) AF: 0.0468 AC: 1564 AN: 33416

American (AMR) AF: 0.00195 AC: 87 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 487 AN: 26088

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86188

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53116

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5754

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1110946

Other (OTH) AF: 0.00451 AC: 272 AN: 60294

GnomAD4 genome AF: 0.0132 AC: 2007 AN: 152256 Hom.: 31 Cov.: 33 AF XY: 0.0122 AC XY: 910 AN XY: 74446

African (AFR) AF: 0.0449 AC: 1863 AN: 41522

American (AMR) AF: 0.00346 AC: 53 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68018

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00592 Hom.: 32

Bravo AF: 0.0146

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000416

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Hereditary spastic paraplegia 30 (2)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (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
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.76
DANN	Benign	0.51
PhyloP100		-1.4
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000074
dbscSNV1_RF	Benign	0.0
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: rs116297894; hg19: chr2-241686737;