rs375180690

Variant names:

• chr2-240769193-G-A
• rs375180690
• NM_001244008.2:c.1437C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240769193-G-A
• chr2-240769193-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001244008.2(KIF1A):​c.1437C>T​(p.Ala479Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,609,758 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. A479A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -3.09
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 30

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-240769193-G-A is Benign according to our data. Variant chr2-240769193-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378043.
• BP7: Synonymous conserved (PhyloP=-3.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000381 (58/152364) while in subpopulation NFE AF = 0.000573 (39/68034). AF 95% confidence interval is 0.000431. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.1437C>T	p.Ala479Ala	synonymous	Exon 17 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.1512C>T	p.Ala504Ala	synonymous	Exon 17 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.1410C>T	p.Ala470Ala	synonymous	Exon 16 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.1437C>T	p.Ala479Ala	synonymous	Exon 17 of 49	ENSP00000438388.1
	KIF1A	ENST00000675932.2		c.1437C>T	p.Ala479Ala	synonymous	Exon 17 of 49	ENSP00000502786.2
	KIF1A	ENST00000675314.2		c.1566C>T	p.Ala522Ala	synonymous	Exon 18 of 50	ENSP00000502584.2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000448 AC: 108 AN: 240952 AF XY: 0.000465

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000616

Gnomad NFE exome AF: 0.000662

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000360 AC: 524 AN: 1457394 Hom.: 0 Cov.: 31 AF XY: 0.000385 AC XY: 279 AN XY: 724568

African (AFR) AF: 0.0000598 AC: 2 AN: 33440

American (AMR) AF: 0.000158 AC: 7 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.000540 AC: 46 AN: 85264

European-Finnish (FIN) AF: 0.000610 AC: 32 AN: 52464

Middle Eastern (MID) AF: 0.000877 AC: 5 AN: 5700

European-Non Finnish (NFE) AF: 0.000362 AC: 402 AN: 1110430

Other (OTH) AF: 0.000432 AC: 26 AN: 60220

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74510

African (AFR) AF: 0.0000721 AC: 3 AN: 41592

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000321

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Hereditary spastic paraplegia 30 (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	-0.58
CADD	Benign	3.9
DANN	Benign	0.60
PhyloP100		-3.1
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs375180690; hg19: chr2-241708610;