rs201861261

Variant names:

• chr2-240758449-C-A
• rs201861261
• NM_001244008.2:c.2493G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240758449-C-A
• chr2-240758449-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001244008.2(KIF1A):​c.2493G>T​(p.Val831Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,611,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V831V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.778
• Publications: 0 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-240758449-C-A is Benign according to our data. Variant chr2-240758449-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379861.
• BP7: Synonymous conserved (PhyloP=0.778 with no splicing effect.

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.2493G>T	p.Val831Val	synonymous	Exon 26 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.2568G>T	p.Val856Val	synonymous	Exon 26 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.2466G>T	p.Val822Val	synonymous	Exon 25 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.2493G>T	p.Val831Val	synonymous	Exon 26 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.2493G>T	p.Val831Val	synonymous	Exon 26 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.2622G>T	p.Val874Val	synonymous	Exon 27 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000312 AC: 76 AN: 243780 AF XY: 0.000332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000590

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000258 AC: 377 AN: 1458998 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 195 AN XY: 725640

African (AFR) AF: 0.0000898 AC: 3 AN: 33400

American (AMR) AF: 0.0000450 AC: 2 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00342 AC: 89 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85720

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000231 AC: 257 AN: 1110620

Other (OTH) AF: 0.000382 AC: 23 AN: 60238

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74358

African (AFR) AF: 0.0000483 AC: 2 AN: 41436

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000458 Hom.: 0

Bravo AF: 0.000230

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	-	Hereditary spastic paraplegia 30 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	KIF1A-related disorder (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	-0.36
CADD	Benign	7.2
DANN	Benign	0.72
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism

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: rs201861261; hg19: chr2-241697866;